On New Year's Eve, Vice-President of the Times Square Alliance Claire Morgan (Hilary Swank) is making the final arrangements for the ball drop with the help of her friend Brandon (Chris "Ludacris" Bridges). Meanwhile, after being nearly run over by a car and denied a vacation, Ahern Records secretary Ingrid (Michelle Pfeiffer) quits her job and offers the deliveryman Paul (Zac Efron) tickets for the Ahern Records Masquerade Ball if Paul helps her complete a series of New Year's resolutions before midnight, which he accepts.
Paul's sister, Kim (Sarah Jessica Parker), is having trouble with her teenage daughter Hailey (Abigail Breslin), who wants to spend New Year's Eve with her friends and her boyfriend Seth (Jake T. Austin) in Times Square. Paul's friend, comic book illustrator Randy (Ashton Kutcher), who hates New Year's Eve after his girlfriend left him on a date, gets stuck in an elevator with Elise (Lea Michele), an aspiring singer who will be providing back-up for musician Jensen (Jon Bon Jovi) in his show at the Ahern Records ball, where he rekindles his feelings for his ex-girlfriend, Laura (Katherine Heigl).
At a nearby hospital, Stan Harris (Robert De Niro), a man in the final stages of cancer who refuses chemotherapy and who only wishes to see the ball drop one last time, is kept company by Nurse Aimee (Halle Berry) and Nurse Mindy (Alyssa Milano) after his doctor (Cary Elwes) reveals he will not last much longer. In the same hospital, a young couple, Griffin (Seth Meyers) and Tess (Jessica Biel), about to have their first child, competes with another couple, James (Til Schweiger) and Grace (Sarah Paulson), for a bonus offered for the family of the first child born in the new year. Elsewhere, Sam (Josh Duhamel), a businessman from Ahern Records, attempts to arrive at the Ahern Records Ball, where he is to deliver an important speech, after his car malfunctions on the other side of New York, all while wondering if he should attend a meeting with a mysterious woman he met and fell in love with on the previous New Year's Eve.
As midnight approaches, one of the billboard lights of the Times Square panel malfunctions, jamming the ball and forcing Claire to call Kominsky (Hector Elizondo), an electrician the company had fired a few weeks prior. Kominsky repairs the ball seconds before midnight, and, in gratitude, Claire leaves him in charge of the operation, and rushes to see the ball drop with her father, Stan. Meanwhile, Nurse Aimee has a video conference with her husband (Common), a soldier serving in Afghanistan.
Paul helps Ingrid complete all the items on her list, and she gives him the tickets. Meanwhile, Randy and Elise bond, and, as they are about to kiss, the elevator is repaired and Elise rushes to Jensen's show. Randy notices she forgot her rubber band and rushes to give it to her. At the Ball, Jensen leaves midway during the show and apologizes to Laura, who accepts him back and leaves with the approval of her assistant, Sous Chef Ava (Sofia Vergara). With Jensen gone, Elise is called to replace him and attracts the attention of the crowd. She kisses Randy, and they start a romantic relationship.
Griffin and Tess have their baby and, although it is born first, they allow James and Grace to have the bonus after discovering they actually have three children. Meanwhile, after being forbidden from attending the celebration, Hailey runs away to Times Square, where she sees Seth being kissed by another girl. Heartbroken, she meets and is comforted by her mother. Seth finds them and apologizes, claiming the girl stole a kiss from him. Hailey forgives him and Seth kisses her. Her mother allows her to go to an after-party. Kim then goes to a restaurant to meet Sam, who had succeeded in delivering his speech. She is the mysterious woman he met one year prior, and they finally discover each other's names.