It's 1967 and Larry Gopnik (MICHAEL STUHLBARG) is a Jewish professor of physics living in the suburbs of Minneapolis/St. Paul who's looking forward to receiving his tenure. While there are annoyances in his day-to-day experience -- ranging from his teenage daughter Sarah (JESSICA McMANUS) constantly complaining about Uncle Arthur (RICHARD KIND) and his perpetual need to drain his neck cyst getting in the way of her washing her hair; younger son Danny (AARON WOLFF) complaining about bad reception for his favorite TV show; or having neighbors ranging from the unfriendly Mr. Brandt (PETER BREITMAYER) who mows across the property line to Mrs. Samsky (AMY LANDECKER) who sunbathes in the nude -- Larry has a good life. Or at least he thinks his does.
His boss at work informs him that there have been some letters arguing against his tenure, while one of his students, Clive Park (DAVID KANG), is trying to bribe him for a passing grade. He doesn't seem to realize that Danny spends all of his money on pot and constantly has to avoid Mike Fagle (JON KAMINSKI JR.), a much larger neighbor and classmate who wants money from the 13-year-old, who isn't thrilled about having to practice for his pending bar mitzvah.
Things get worse, however, when Larry's wife, Judith (SARI LENNICK), informs him that she's fallen in love with their friend, Sy Abelman (FRED MELAMED), and wants a divorce, but not before she makes him move out and into a nearby motel. While seeking legal advice from a divorce lawyer (ADAM ARKIN), Larry wonders why God seems to be punishing him, resulting in a number of visits to various rabbis.
As he must contend with the disappointments piling up all around him, Larry hopes to find a reason or at least some sort of meaning to his world being upended.