Goody (Alicia Silverstone) is a vampire who was transformed in the 1880s. Stacy (Krysten Ritter) is a vampire who was transformed in the 1990s and has been Goody's roommate ever since. Goody is embarrassed about her age so she told Stacy she was transformed in the 80s and Stacy has assumed that means the 1980s. They live in an apartment in New York City going to night clubs in hopes of finding true love. Stacy also attends night class at college. One day, she flirts with a fellow classmate only to learn his name is Joey Van Helsing, as in the son of Dr. Van Helsing (Wallace Shawn).
Meanwhile, Dr. Van Helsing is on a mission to rid New York of vampires and he's convinced Stacy is a vampire when he has her over and notices her ice cold hands and her pale white skin.
We are also introduced to Cisserus (Sigourney Weaver). She is a stem vampire, which means she has the ability to kill humans or turn them into fellow vampires. She is Goody and Stacy's stem. Goody and Stacy also learn that if Cisserus were to ever die, they would revert back to human form at their true age.
While Cisserus regularly kills people to satiate her thirst for blood, Goody and Stacy are disgusted by the idea and instead drink rat blood and attend an AA like support group for vampires not wanting to drink human blood. The meetings are also attended by Vlad the impaler (Malcolm McDowell) who knits sweaters and dispenses fatherly advice to some of the younger vampires.
There's another subplot about a former 60s activist named Danny (Richard Lewis) who is now an ACLU lawyer. Back in the 60s, he and Goody were an item but she skipped out because she didn't know what he would do once he learned about what she was. He is now married to Angela (Marilu Henner) who is on her deathbed from cancer. While Goody considers resuming her relationship with Danny once he learns that she is a vampire and is surprisingly okay with it, she eventually has one of her stem vampire friends turn Angela into a vampire so she and Danny can have more time together.
Stacy and Joey begin dating and he finds out that she's a vampire. While initially bothered by it, he eventually accepts it and keeps dating her. Then one day she starts throwing up and Goody eventually figures out she's pregnant. Goody talks to Vlad about it and he explains that a pregnant vampire can't carry a baby and the unborn child will die after about a week. Goody proceeds to tell Stacy the news that her pregnancy won't last only to find out that Stacy actually liked the idea of being a mommy.
Goody realizes the baby's only shot at life is to kill Cisserus. Unfortunately, nobody knows where her coffin is. She told Goody earlier that it's a place in NYC where nobody ever bothers to visit. Then one night Goody and Stacy are watching TV and hear Groucho Marx ask someone who was buried in Grant's Tomb and they figure out that Grant's Tomb is a New York landmark that nobody ever visits.
She approaches Dr. Van Helsing and gets his attention by explaining that he's about to be a grandfather. Goody tells him that they need to find and kill Cisserus before the baby dies. She also tells him that she lived in the 1800s and saw her husband die and after becoming a vampire lived with her two children until they died of old age. She didn't bother getting in touch with her grandchildren since she thought she would just frighten them. Van Helsing uses her information to track down her descendents. She has several great-great-grandchildren. One of them didn't turn out so successful but the rest became doctors.
Goody, Stacy, Van Helsing, and some of his assistants approach Grant's Tomb and decapitate Cisserus.
Afterwards, Stacy notices that she changes very little. She explains that she always ate healthy and never tanned.
Then she looks over at Goody and notices that she is slowly getting older and older. Then Goody confesses that she was not from the 1980s but the 1880s and she knew that she wouldn't survive once Cisserus died but she wanted Stacy to have her baby and she is getting tired of living anyway.
She also admits that she was about to kill herself by walking into the sunlight right before Stacy became her roommate. She thanks Stacy for the last 20 years and they walk together to Times Square. As they stand there, Goody continues to age rapidly and her life flashes before her eyes as she peacefully dies.
The final scene shows Stacy and Joey some time later playing with their daughter, who they named Goody Van Helsing.