"Standing Up, Falling Down" follows standup comedian Scott (Ben Schwartz), whose career has crashed and burned after four years of chasing his dream in Los Angeles. Left with little money, he has no choice but return to his parents' house in Long Island.

While trying to figure out what to do next, Scott pines after his ex, Becky (Eloise Mumford), a successful photographer who has since married a former mutual friend. On a night out at the bar, Scott strikes up an unlikely friendship with an eccentric dermatologist, Marty (Billy Crystal), who has regrets of his own.