They had been without a GM since Coach Pat Quinn gave up the dual role on June 27. It was a joint decision made by Quinn and Maple Leafs Sports & Entertainment Ltd. CEO Richard Peddie.
Former New York Rangers GM Neil Smith and Hockey Canada President Bob Nicholson also were finalists for the position.
At 36, Ferguson will be the youngest general manager in the NHL. He served as the director of hockey operations for St. Louis since 2001 after five years as the team's assistant GM.
"I've been preparing for this my entire life," Ferguson said at a news conference. "Make no mistake, I am here to win. I know that my mandate is to make this club the best in the NHL on and off the ice."
Quinn, who has two years left on his contract, will remain as coach. He took over the coaching duties on June 26, 1998.
Toronto, which has not won the Stanley Cup since 1967, finished fifth in the Eastern Conference last season and lost to Philadelphia in the first round of the playoffs.