In the series, set in a fictional 1960s advertising agency, he plays a suave, married advertising executive with an obscure past.
Alan Taylor and Mad Men creator Matthew Weiner initially thought Hamm was too handsome for the role but ultimately decided, "it was perfect to cast sort of the perfect male in this part".
And as soon as I said that, it's like I started working right away.
During 2000, he made his feature movie debut in the space adventure movie Space Cowboys.
The next year, he had a minor role in the independent comedy, Kissing Jessica Stein (2001).
Robert Bianco of USA Today was complimentary of Hamm's performance, describing the actor's interpretation of Draper as a "starmaking performance".
The story concerns a group of friends whose lives are changed as the couples in the group begin to have children.
He was in the animated comedy Minions, as the voice of Herb Overkill. Hamm appeared in the Sponge Bob Square Pants episode "Factory Fresh".
In 2017 Hamm joined the BBC and Amazon's television adaptation of Terry Pratchett and Neil Gaiman's Good Omens as the Archangel Gabriel.
Later she moved to Chicago and worked with the Piven Theatre Workshop.
She also performed on National Public Radio in the production of the radio play Born Guilty.
In an interview discussion about his relationship with Westfeldt, Hamm said: "We may not have a piece of paper that says we're husband and wife, but after 10 years, Jennifer is more than just a girlfriend. To me, people get married when they're ready to have kids, which I'm not ruling out." Hamm also narrates the Amazon NFL documentary series All Or Nothing since 2015.