Whannell appeared in Episode 4, Season 1 of the RMITV production Under Melbourne Tonight presents What's Goin' On There? on 10 June 1998

In 2003, Whannell appeared in a minor role in The Matrix Reloaded, as well as in the video game Enter The Matrix as the character "Axel".

While in film school, Whannell met James Wan, who would eventually go on to direct the horror film, Saw (co-written by Wan and Whannell) in 2004. After making a short film to showcase the intensity of the script, the feature film was made and became a low-budget sleeper hit in late 2004. Whannell played Adam Stanheight in the film, one of the main characters. The popularity of Saw led to a sequel, Saw II, which was directed and co-written by Darren Lynn Bousman, and on which Whannell co-wrote and revised Bousman's original script, titled The Desperate. Whannell also served as an executive Producer.

Around the same time, Whannell returned to collaborate with Wan; they wrote a film called Dead Silence, which Wan directed. It was originally slated for a 2006 release, but small problems with the title pushed the release date back to March 2007. In 2006, the duo composed the story for Saw III; Whannell wrote the screenplay for the third time. It was again directed by Bousman and was released on 27 October 2006. Whannell has a featured cameo, reprising his role as Adam. Saw III grossed $33,610,391 on its opening weekend, making around $129,927,001 worldwide (after 38 days in cinemas) and is currently the most successful Saw film to date.

In 2008, Whannell took off his "writing hat" to perform alongside Nathan Phillips in Dying Breed, a low-budget Australian horror film about a team of Zoologists exploring the Tasmanian wilderness to locate a creature thought extinct, the thylacine, aka Tasmanian tiger. Instead, they wander into the domain of cannibals who retain their ancestor Alexander Pearce's taste for human flesh, and become prey.

Whannell and Wan are the creators of the Saw franchise. Whannell wrote the first installment, co-wrote the second and third installments, was Producer or executive Producer for all the films, and appeared as the "Adam Stanheight" character in four of the installments. He was also the Writer of the Saw video game (2009), and co-writer of the 2014 film Cooties.

In relation to the Saw franchise, Whannell stated, also in 2011:

Media reports were published in mid-2013 in regard to Cooties, a film project that Whannell is an executive Producer, actor and Screenwriter for. The film's plot concerns an extreme virus that infects an isolated elementary school. Whannell made his directing debut on the sequel Insidious: Chapter 3 (2015), which he also wrote.

In 2014, Whannell expressed possible interest in returning to the Saw franchise; however, in a November 2013 post on his personal blog, Whannell described a new chapter beyond his partnership with Wan, as the Director had finally reached his goal of making epic-style blockbuster productions. Whannel explained: "Now, he’s off making the films he’s always wanted to make - the big ones. I have no doubt that his name will be added to that special club of film Directors that he’s always admired very soon. I’m so happy for him, like a proud father. And that is why it is the end of an era." Whannell also added that he doesn't rule out collaborating with Wan again, but he felt like he needs to direct a film for the first time.