After not being drafted by an NFL team, Calvillo started his Canadian Football League career in 1994 with the US expansion Las Vegas Posse.

[5] After the Posse folded a year later in the CFL U.S. expansion experiment, Calvillo was selected first overall by the Hamilton Tiger-Cats in the dispersal draft.

On October 25 against the Montreal Alouettes, he threw for 542 yards, which was the highest passing yardage total in the CFL that year, and rewrote the Hamilton single game record.

On June 26, in a game against the Hamilton Tiger-Cats, Calvillo surpassed Danny McManus to become the second-all-time leading passer in the CFL.

On July 31, in another game against the Hamilton Tiger-Cats, Calvillo became the fourth quarterback in league history to reach 300 career touchdown passes.

On August 15, 2008, in a game against the Toronto Argonauts, Calvillo became the second quarterback in CFL history after Damon Allen to reach 4,000 career pass completions.

On July 23, 2009, he surpassed Canadian Football Hall of Famer Ron Lancaster's 334 career touchdown passes to move into second place all time.

Calvillo led Montreal to a 16-point fourth quarter comeback victory in the 97th Grey Cup on Nov. 29, when the Alouettes defeated the Saskatchewan Roughriders 28–27 on a last-second field goal known as the "13th Man" finish.

In a post-game interview, he revealed that he would be undergoing off-season surgery to remove a lesion on his thyroid that was discovered after he injured his sternum during the season.

[9] On July 15, 2011, in a game against the Toronto Argonauts, Calvillo completed his CFL record 395th career touchdown pass to Éric Deslauriers.

[11] Then, on October 10, 2011, Calvillo completed a touchdown pass to Jamel Richardson to become professional football's all-time leading passer, in the Alouettes' third and final game against the Toronto Argonauts that year.

In Week 8 of the 2013 CFL season, Calvillo left the game after taking a hit from Saskatchewan's Ricky Foley.

[15] On October 18, 2013, the Montreal Alouettes general manager and head coach Jim Popp announced that Calvillo would not be returning to play for the remainder of the 2013 season.

[21] Going into the 2016 season, Calvillo was named offensive coordinator with Jacques Chapdelaine as his special advisor as he grew into the role.

[24] The hire reunited Calvillo with his former general manager Jim Popp, and head coach Marc Trestman.

On December 19, 2018, Calvillo was named as the assistant head coach for the Montreal Carabins football team in U Sports.