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 Police Officer Brendan (Chris "Ludacris" Bridges). Meanwhile, after being nearly run over by a car and denied a vacation, Ahern Records secretary Ingrid Withers (Michelle Pfeiffer) quits her job and offers the deliveryman Paul Doyle (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 Doyle (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 Anderson (Jake T. Austin) in Times Square. Paul's best 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 Daniel Jensen (Jon Bon Jovi) in his show at Times Square. He also prepares to perform 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 named Griffin (Seth Meyers) and Tess Byrne (Jessica Biel) are about to have their first child, and they compete with another couple, James (Til Schweiger) and Grace Schwab (Sarah Paulson), for a bonus offered to the family of the first child born in the new year. Elsewhere, Sam (Josh Duhamel), a businessman from Ahern Records, attempts to go to the Ahern Records Ball, where he is to deliver an important speech, after his car malfunctions outside New York City, all the 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.
In the early evening, one of the LED panels on the Times Square Ball malfunctions, jamming the ball and forcing Claire to call Kominsky (Héctor Elizondo), an electrician who the company had fired a few weeks prior. Kominsky repairs the ball 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 Chino (Common), a soldier serving in Afghanistan. Stan passes away just after the ball drops and a chorus of Auld Lang Syne, with Claire holding his hand.
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 by the building superintendent (James Belushi) and Elise rushes to Jensen's show. Randy notices she forgot her rubber bracelet and rushes to give it to her. At Times Square, Jensen leaves midway during his show to return to the Ahern Ball to apologize to Laura, who accepts him back and leaves with the approval of Sam. 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 lie to allow James and Grace to have the bonus after discovering they already have two other children to provide for. Meanwhile, after being forbidden from attending the celebration, Hailey runs away to Times Square, where she sees Seth being kissed by another girl, Lily, unaware that he had been kissed against his will. Heartbroken, she meets and is comforted by her mother. Seth finds them and apologizes, revealing Lily to have stolen a kiss from him. Hailey forgives and kisses him. 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.