Carl, a bank loan officer, has become withdrawn since his divorce from Stephanie. He has an increasingly negative outlook on his life and routinely ignores his friends Peter and Rooney. On the advice of an old colleague, Nick, Carl attends a motivational seminar that encourages people to seize the opportunity to say "Yes!" At the seminar, Carl meets inspirational guru Terrence, who tells him to enter a "covenant with the universe" and say yes to anything asked of him.
Later, Carl says yes to a homeless man's request and is stranded out-of-gas and with no battery on his cell phone in Elysian Park. Disillusioned, he hikes to a nearby gas station where he meets Allison, an unorthodox young woman. She gives him a ride back to his car on her scooter and kisses him before leaving. A few days later he is offered oral sex by his elderly neighbour Tillie in return for helping her put up shelves; when he refuses and immediately experiences bad luck he returns and surprisingly enjoys the moment.
Believing that he must say "yes" or suffer the consequences, Carl starts to seize every opportunity that comes his way. He renews his friendships with Peter and Rooney; builds a bond with his nerdy boss, Norman; assists Peter's fiancée, Lucy, with her bridal shower; attends Korean language classes; and much more. Accepting a band flyer outside of a coffee shop, he sees an idiosyncratic band called Munchausen by Proxy; the lead singer is Allison. He is charmed by her quirkiness; she is delighted by his spontaneity and they begin dating. He earns a corporate promotion at work and, making use of his guitar lessons, plays Third Eye Blind's song "Jumper" to persuade a man not to commit suicide.
Carl and Allison meet at the airport for a spontaneous weekend excursion. Having decided to take the first plane out of town, regardless of its destination, they end up in Lincoln, Nebraska, where they bond more. Allison confesses her love for Carl and asks him to move in with her and he hesitantly agrees. While checking in for the return flight, Carl and Allison are detained by FBI agents who, due to various coincidences in Carl's recent behaviour, have profiled him as a potential terrorist. Peter travels to Nebraska as Carl's attorney and explains the situation, revealing the truth to Allison at the same time. She begins to doubt whether his commitment to her was ever sincere. Deciding that she can no longer trust him, she leaves Carl and refuses to return his phone calls.
Carl's life takes a turn for the worse and he almost forgets about Lucy's shower. He manages to arrange a major surprise party, as well as set up Norman and Rooney with Soo-Mi and Tillie respectively. After the party Carl receives a tearful phone call from Stephanie, whose new boyfriend has walked out on her. When he goes to her apartment to comfort her, she kisses him and asks him to spend the night with her. After Carl emphatically says no, his luck takes a turn for the worse.
Deciding he must end the covenant, Carl returns to the convention centre and hides in the backseat of Terrence's convertible so he can be released. However, he reveals himself while Terrence is driving, startling him and causing an oncoming vehicle to collide with them. After Carl regains consciousness in the hospital, Terrence tells him the covenant was not real - it was merely a starting point to open Carl's mind to other possibilities, not to permanently take away his ability to say no if he needed to.
Freed from this restraint, Carl finds Allison teaching her sports-photography lesson and admits that he is not ready to move in with her just yet, but that he genuinely loves her, and they reconcile with a kiss as Allison's students take pictures.
Carl later persuades the attendees of Terrence's next seminar to donate the clothes off their backs to charity, and Terrence is greeted by an entirely nude convention centre.
Jim Carrey as Carl
Zooey Deschanel as Allison
Bradley Cooper as Peter, Carl's best friend
John Michael Higgins as Nick
Rhys Darby as Norman, Carl's boss
Danny Masterson as Rooney, Carl's other best friend
Fionnula Flanagan as Tillie, Carl's elderly neighbor
Terence Stamp as Terrence
Sasha Alexander as Lucy, Peter's fiancée
Molly Sims as Stephanie, Carl's ex-wife
Aaron Takahashi as Lee
Sean O'Bryan as Ted
Spencer Garrett as Multack
Rocky Carroll as Wes
Vivian Bang as Soo-Mi
Jarrad Paul as Reggie
Luis Guzmán as Jumper
Brent Briscoe as Homeless Guy
Maile Flanagan as Janet
Danny Wallace as Conventioner (uncredited)
Trisha Paytas as Conventioner (uncredited)
based loosely on the 2005 memoir of the same name by humorist Danny Wallace,