Pádraic (Colin Farrell) and Colm (Brendan Gleeson) have been friends for years. It's 1923, and they live on the sparsely populated island of Inisherin. One day when Pádraic goes to call on Colm for their usual 2 p.m. walk to the pub, Colm pretends he doesn't see or hear him. He stays holed up in his shack, sitting in a chair, turned away from the window.

When Colm finally makes his way to the bar, he tells Pádraic that he doesn't like him anymore. He calls him dull, and says he has better things to do with his time than listen to Pádraic's idle and meaningless chatter. Stunned, and heartbroken, Pádraic can't understand what's happening. He tries to smooth things over, but Colm isn't having any of it and won't even let Pádraic sit with him.

As Pádraic tries to make sense of it, he turns to his loving sister Siobhán (Kerry Condon) and the socially awkward Dominic (Barry Keoghan), but they can't understand why Colm has done this to Pádraic, who is innocent and kind. But Colm's cruel actions eventually bring about alarming consequences for both of them.