It's Panda's birthday, and he asks Iris to take him to the biggest party in history: the millennial celebrations in San Francisco on New Year's Eve, 1999. However, in his impatience to get there, he rushes Iris out of the Prince of Wales pub with her drink still unfinished and harangues her as she tries to plot out the correct course. Irritated, she starts the bus moving so sharply that her unfinished gin and tonic topples and spills directly into the bus's engines, creating a multi-dimensional rift in the space/time vortex. The bus crashes, and when Panda recovers, there's no sign of Iris -- but there is another panda in the bus, a preening, upper-crust dandy who identifies himself as Lionel Pandeau and who claims that Iris staggered out of the bus, no doubt to go throw up. Pandeau arrogantly identifies himself as a more elegant, wittier, and richer alternative version of Panda himself, whom Pandeau regards as a bumpkin country cousin. Offended, Panda threatens to sue his alternative self for impersonation, or possibly copyright infringement.
The bus has reached its intended destination, and the San Francisco police take the unconscious Iris to hospital, assuming that she's passed out drunk. Her vital signs are all over the place, and Dr George Strangeways assumes that the X-rays have been double exposed when they seem to indicate that his patient has two livers. Iris comes to, but to George she seems disorientated and confused; while trying to work out where she is, she recalls visiting Henry VIII, travelling with her grandson Steven or her niece and nephew Jenny and Jimmy, living for centuries, having several different bodies, taking Jane Austen to a party on the Moulin Rouge space station near Betelgeuse, and visiting San Francisco on a past occasion to transport two humpbacked whales into the future. Convinced that she's in need of a psych consult, George tries to ask her a few easily-answered questions, but Iris doesn't know or care who the current President of the United States is; the only worthwhile one was Honest Abe, who once helped her fight off a Martian invasion. Iris then notices how handsome her young doctor is and begins trying to flirt with him, and George, convinced that she's suffered head trauma, agrees to grab a coffee with her in order to keep her from checking herself out.
Pandeau is unsure whether Iris's bus is a post-modern ironic statement or just a bloody mess, but he's equally certain that it somehow holds the secrets of safe trans-dimensional travel. This could be worth a fortune, if he can convince Panda to explain how it happened. Panda remains silent and tries not to think about the truth when he realises that Pandeau can read his thoughts; however, since they are different aspects of the same person, Pandeau knows all of Panda's weaknesses, and he breaks his other self's resolve by tying him up and threatening to give him a terrible haircut. Panda caves in and reveals the truth about the gin and tonic, and Pandeau begins to tinker with the bus's controls, revealing that he intends to take over the world with an army of pandas.
Iris's attempts to flirt with George over coffee are interrupted when they hear an old woman screaming in the gift shop. The dazed woman explains that her grand-daughter is in the hospital for a nose job, and that the stuffed toy the old woman intended to buy as a gift bit her and ran away. Iris notices movement behind the flowers, and George is shocked when a stuffed toy indeed growls at her and runs off. Iris and George pursue the toy into the lower levels of the hospital, near the morgue and blood stores, and Iris lures it out of hiding by pricking George's thumb with a sharp needle, using his blood as bait. The toy attacks, but Iris drives it off with a spray of tonic water from a bottle in her handbag. Iris identifies it as a vampire panda from another dimension, and explains that it's gone to lick the sticky tonic water off its fur. Meanwhile, news reports are coming in from throughout the city of further attacks by 10"-high pandas, which the police have put down to millennial hysteria.
Pandeau successfully adjusts the bus's controls, but remains contemptuous both of the bizarre vehicle and of Panda, who seems content to be a camp comic sidekick to an old souse rather than ruler of the world. Pandeau starts up the engines and takes the bus to a suitable vantage point from which to look down upon the chaos; at the clichéd but nevertheless dramatic stroke of midnight, he intends to smash open a rift between dimensions, letting through panda of far more dangerous varieties than mere pompous megalomaniac art critics. Panda manages to struggle out of his bonds, but when he attempts to storm out of the bus to find Iris, he ends up dangling from the doors, 700 feet above the ground. Pandeau has parked the bus on a pylon of the Golden Gate Bridge, and as he laughs maniacally, Panda realises that his doppelganger is completely mad.
While George tries to wrap her head around the fact that he's been attacked by a stuffed vampire panda from another dimension, Iris sees a news report about the bus's appearance on the Golden Gate Bridge, which supports her suspicions that her own Panda must be involved in these events. The biggest street party in history is blocking her path to the bridge, and George suggests taking the hospital helicopter. It's only supposed to be called out for dire emergencies, but Iris identifies Bill the security guard by name, divines that his marriage is going through a rough patch, and urges him to go home to settle things with his wife while he still can. Stunned by her preternatural knowledge, Bill rushes home to do as she suggested, and Iris then admits to George that she saw Bill's name on his tag, noticed his wedding ring and the food stains on his trousers, and deduced that only someone who was having troubles at home would be eating take-out food at work on New Year's Eve. She is still trying to flirt with George, but he tells her that he lives with his mother, works long hours, and finds the dating scene immature. Disappointed by his rejection, she pilots the helicopter to the bridge, and before George realises what she's doing, she hands him the controls and jumps out.
Pandeau safety-pins Panda to the bus seat and starts searching for Iris's stores of gin, but Panda gets to them first and scoffs the lot. This seems to foil Pandeau's plans, until the now tipsy Panda inadvertently reveals that there's a hidden stash elsewhere on the bus. Once again, he gives in and reveals its location when threatened with a nasty haircut. Iris then jumps onto the bus, and she and Panda both put on brave fronts, pretending that they're not at all relieved to see that the other is alive and well. Unfortunately, Panda must then confess that he's given away everything his evil doppelganger needs to reopen the rift. Pandeau has already deduced that the rift draws in alternative versions of whomever is standing next to it when it opens; it didn't work with Iris because there is only one Iris Wildthyme in all the multiverse, but when Pandeau opens the rift, he will summon an army of alternative himselfs with which to conquer not only this world but all alternative Earths as well. Iris pleads with him to reconsider, but he mocks her and dumps all of her remaining gin straight into the bus's engines.
George is trying to keep the helicopter aloft while simultaneously fielding a phone call from his mother when the rift opens. Bat-winged pandas from five million years in the future and three dimensions to the left swarm out over San Francisco, and a giant Pandazilla stomps across the city, heading straight for the Golden Gate Bridge. To Iris's horror, the helicopter crashes into Pandazilla, exploding but only slightly damaging the giant monster. Deeply upset, Iris demands to know what makes Pandeau think that Pandazilla will spare him, and despite Pandeau's insistence that the other pandas will naturally recognise him as their superior, it's clear that he's not entirely certain. Nevertheless, he refuses to surrender, but as he attacks Iris, George pulls himself into the bus and restrains him, revealing that he lost control of the helicopter and jumped out before it crashed into Pandazilla.
Iris plans to counteract the effects of the gin by pouring tonic water into the bus's engines, but nothing happens; the rift is too large, and the only way to close it now is to pour tonic water directly into the rift itself. Panda volunteers to do so; Pandeau is convinced that Panda is too content to be a sidekick to go through with it, but Panda has decided that it's worth risking his life just to put a stop to his pompous alternative self. He gives Pandeau a right good punch up the hooter, and before Iris can intervene, both pandas fall off the bus and into the rift, taking the tonic water with them. The rift closes up, and all of the pandas menacing San Francisco vanish along with it.
In the aftermath of the invasion, one of the mysterious top-secret organisations that deals with this sort of thing releases a statement that the bridge was damaged by a fireworks stunt gone wrong. Iris believes that the pandas have all gone back to where they came from, including her own, but she admits that she and Panda were always so busy having fun that she never bothered to learn his origins. She invites George to help search for her missing friend, but he turns her down, claiming that he has a life here and isn't cut out for Iris's brand of excitement. Also, he admits that he simply doesn't fancy her. Iris takes it well, and after bidding a fond goodbye to George, she sets off in search of Panda... and accidentally spills her drink as she kicks the bus into motion. Elsewhere in time and space, as Panda waits impatiently for Iris to come to his rescue, he hears the sound of sleigh bells...