Odenkirk learned that he had plaque buildup in his heart in 2018, but said he received conflicting medical advice on treating it. The 2021 cardiac event occurred when "one of those pieces of plaque broke up." Since his heart attack, Odenkirk has been vocal about how the health scare changed his life.

Odenkirk's friendship with Ben Stiller, with whom he briefly shared an office at SNL, would lead to his being hired for the cast of The Ben Stiller Show in 1992.

Robert John Odenkirk was born in Berwyn, Illinois, to Barbara (Baier) and Walter Odenkirk, who worked in printing. His ancestry includes German and Irish. He grew up in Naperville, IL, the second of seven children. He worked as a DJ for WIDB, his college radio station at Southern Illinois University Carbondale.

As of 2024, Bob Odenkirk's net worth stands impressively at $16 million. This figure places him in a unique position when compared to his peers in the comedy and acting industry. For instance, Odenkirk's net worth is notably higher than that of fellow comedian and writer David Cross, estimated at around $10 million.