Jeff (Jason Segel) is a basement-dwelling 30-year-old searching for some kind of meaning in his life. He is preoccupied with seeing and understanding signs around him, and has a sad, defeated manner about him. He receives a phone call--a wrong number--where the caller berates Jeff, insisting to speak to a Kevin. Jeff is shaken by the call, but soon receivers another call from his mom, Sharon, (Susan Sarandon) asking him to go buy some wood glue and fix a broken cabinet. It is her birthday, and this is her desired gift.
Meanwhile, his brother Pat (Ed Helms) is at his apartment with his wife Linda (Judy Greer), revealing that he has purchased a Porche without her knowledge. Linda is angry, as they'd been saving to buy a home.
Jeff follows a series of possible signs, leading him to run into Pat at a Hooters restaurant. Pat, having spoken with their mother, reluctantly agrees to try and "help" Jeff, somehow. Pat, slightly drunk and wishing to show off his new Porshe, ends up crashing into a tree after some reckless driving. It is here they see his wife headed to lunch with another man.
Jeff and Pat follow them, with Pat convinced Linda is having an affair.
Pat cajoles a reluctant Jeff to spy on Linda and her lunch date. Jeff is not left with an impression that they are having an affair, only that Linda is deeply unhappy in her marriage. He is unable to convince Pat of this, though.
Jeff continues to look for signs around him, jumping aboard a truck emblazoned with "Kevin's Kandies" on the side. Pat stumbles across his wife's car at a nearby hotel, where the truck Jeff was riding on eventually ends up. Jeff is delighted to have been led right back to Pat, believing these signs are leading somewhere important.
They find and confront Linda and her companion, who are simply talking. After some harsh words between them, Linda all but asks Pat for a divorce and leaves. He is crushed. Pat and Jeff catch a taxi together, determined to catch up with Linda so that Pat can declare that he wants to save the marriage.
Meanwhile, Pat and Jeff's mom is at work, where she has a secret admirer sending her instant messages. She is excited but doubting of this development, not having dated in over 15 years since her husband died. Eventually, she deduces that her admirer is her close female friend, Carol, with whom she works. Though Sharon insists that she only likes men, Carol eventually convinces her to skip out on work for a day in New Orleans (they are in Baton Rouge) after a touching romantic gesture and a kiss.
All their paths converge in a traffic jam on a bridge leading out of Baton Rouge. As they all sit in separate cars, waiting for the traffic to clear, Jeff seems to sense a sign.
He jumps out of the taxi he is sharing with Pat, and runs across the bridge at breakneck speed, encountering an accident where a car has plunged into the lake below. He jumps into the water without hesitation, and shortly emerges carrying two young children. They yell that their dad is still in the submerged car, and Jeff dives again to save the dad. Pat, Linda, Carol, and Sharon all run to where Jeff has jumped in, witnessing the entire scene. Pat jumps in after Jeff when he doesn't emerge with the dad (who has come up on his own).
Pat drags Jeff out of the water, and onto an approaching Coast Guard boat. They perform CPR on the unresponsive Jeff, who is eventually revived. All reunite on a nearby dock, and there is a sense that everything is going to be OK. They later celebrate Sharon's birthday at home with cake.
Jeff is seen watching TV coverage of the accident and his heroism (he is not named, it is implied that he didn't give his identity to anyone). The dad of the kids is revealed to be a local councilman named Kevin.
Jeff goes upstairs and uses the wood glue to fix the broken cabinet, with a contented smile on his face.