After a gap year, Blake enrolled at the University of Melbourne in a Science/Commerce double degree. "I'm interested in artificial intelligence and computer science. That stuff still fascinates me." He says. However, a few weeks into the semester he met Andy Lee: "That was the turning point. The wheels quickly fell off my academic career." Blake eventually dropped out of university to pursue a career in comedy alongside Lee. Blake's first experience with comedy was when he entered a competition at university. He was broke at the time, and hoped to win the $500 first prize. His stand-up performance earned him third place and qualified him for a statewide universities' final, which he did win.
Blake's girlfriend, Anna Jennings-Edquist, is an actress who formerly starred in the Australian soap opera Neighbours. As of November 2007 they had been dating almost 3 years. Hamish is an atheist.
The Hamish and Andy Show premiered on the Seven Network in March 2005, but failed to achieve ratings success and was cancelled after two weeks. Reviewers acknowledged the duo's talent, but criticised the show as "poorly executed". Blake says that while working on the show was a fun experience, they had little control over what happened and the way it went forward. Following the cancellation of The Hamish and Andy Show, they created a short mockumentary titled The Greystone 2800 about a couple who accidentally bought an open display home after failing to read the fine print on a housing purchase. The film won the Melbourne Comedy Festival Short Film competition and attracted the attention of comedian Rove McManus. This led to some small spots on McManus' Network Ten show Rove Live.
McManus's company, Roving Enterprises, also helped the duo develop Real Stories, a mock current affairs show that aired on Network Ten in 2006. Blake says that the experience of creating Real Stories was much more enjoyable than The Hamish and Andy Show because they had greater control over the series. Blake and Lee wrote, acted, directed, filmed and produced the show with input from Ryan Shelton and Tim Bartley.
In 2006, Blake and Lee debuted a national drive-time radio show titled Hamish & Andy on the Today Network. The show quickly gained popularity, finishing 2006 with almost one million Melbourne listeners, ahead of 3AW's popular radio host Derryn Hinch. As of August 2008, Blake and Lee's show was rating number one in four out of Australia's five major capital cities.
In September 2008, it was announced that they would make a guest appearance on Ten's Are You Smarter Than A Fifth Grader?, which is hosted by McManus.
He has a monthly column in the Australian women's magazine Cosmopolitan. He was also the winner of the TV Fugly Award for Spunkiest Male TV Personality in 2008.