After graduating from McGill, Mathison began working as a model and started acting in commercials in Canada, the U.S. and Europe. This led to taking acting classes and the beginning of his acting career in Toronto.
Mathison made his feature film debut in 54. He followed up this appearance with a leading role in the Canadian independent movie Washed Up. About this time, December 1997, he was hired to play the role of Ryan Lavery on All My Children filming his first scenes on December 15. Mathison first appeared on-screen in the January 12, 1998 episode.
Mathison won the Soap Opera Digest Award for Outstanding Male Newcomer in 1999 and earned Daytime Emmy Award nominations for Outstanding Supporting Actor in 2002 and 2005. In 2000, Mathison was named by People magazine as one of "America's 100 Most Eligible Bachelors".
In 2007, Cameron was on season five of Dancing with the Stars where he placed 5th with pro Edyta Śliwińska.
After working freelance with Good Morning America for several years, Mathison signed with GMA in January 2009 as a regular correspondent. Mathison worked on many events for GMA: The Oscars, Grammys, Golden Globes, American Music Awards, MTV Movie Awards, MTV Video Music Awards, and the Country Music Awards. Mathison continued to work as a host and correspondent for GMA, the Emmy-nominated series Ultimate Proposal, and the renovation reality show Game of Homes.
Mathison also continues to act in both comedic and dramatic roles. He has appeared on Castle, Desperate Housewives, Hot in Cleveland, Drop Dead Diva, the EXes, and numerous independent and television movies. In 2014, Mathison joined the Hallmark/Crown Media family. Mathison signed on to appear in 9 movies based on the Murder She Baked novels starring opposite Alison Sweeney.
In April 2015, Mathison signed with CBS's Entertainment Tonight. He is currently serving as a full-time correspondent and weekend co-anchor for the entertainment newsmagazine. On July 26, 2018, Mathison was named the new co-host of Home and Family, alongside Debbie Matenopoulos; he assumed his position in September with the launch of the seventh season.
On April 5, 2021, various sources broke the news that Mathison will join the cast of General Hospital in a mysterious role. Mathison had a few free days during the week and called Frank Valentini to see if he had a role available. It was later revealed that Mathison will join the cast in the summer. In June, rumors began to surface that Mathison will be taking over the role of Drew Cain, a role that was previously played by Billy Miller.
On August 6, 2021, Mathison confirmed on GMA3: What You Need to Know that he will NOT be reprising his All My Children role as Ryan Lavery on General Hospital, but that he will be portraying a new character.
On August 8, 2021, it was confirmed by Daytime Confidential and Entertainment Weekly that Mathison will indeed be playing a recast Drew. Although Mathison’s voice was first heard as Drew on August 16, 2021, he made his first appearance as Drew on August 17, 2021.
On November 19, 2021, Mathison revealed that he was preparing to portray Ric Lansing before finding out at a meeting with Frank Valentini and head writers Chris Van Etten and Dan O'Connor that he would be Drew.