Carl Gunnarsson, John-Michael Liles, Phil Kessel and Mikhail Grabovski scored for the Maple Leafs, who have been outscored 28-10 in the five meetings with the Bruins.
The Leafs played more than half the game with a short bench after losing forwards Joffrey Lupul and Colby Armstrong early in the second period. Lupul appeared to suffer a wrist injury after taking a check from David Krejci while Armstrong was bloodied in a fight with Dennis Seidenberg.
Toronto lost in Randy Carlyle's home debut four days after he replaced the fired Ron Wilson. After winning his debut at Montreal on Saturday night, the new coach put his team through two lengthy practices with a major point of emphasis trying to get the Leafs to play a more conservative defensive game.
The middle period offered a glimpse of the tougher brand of hockey the Leafs are expected to play under Carlyle, resulting in three fights. However, it also cost Toronto the game.
After Liles put the Leafs ahead 2-1 with a power-play goal at 57 seconds, Boston quickly scored twice. Seguin tipped Zdeno Chara's shot in at 2:02, and Kelly scored on a rebound past Jonas Gustavsson, who was bumped out of position by a hard-charging Caron, at 2:43.
A 5-on-3 power play allowed the Leafs to tie it, with Kessel getting his 33rd of the season at 9:52.
Boston had another scoring flurry as Caron tapped home a pass from Chara at 13:34 and Seguin converted a one-timer at 14:09 for a 5-3 lead heading to the third period.
Grabovski pulled the Leafs within one as he went in alone and beat Thomas at 13:13, but Toronto Leafs couldn't tie it again despite getting a two-minute power play late.
Gunnarsson opened the scoring by beating Thomas high with shot at 3:01 of the first period.
Caron tied it with 6:02 to go in the period.
NOTES: Boston last won consecutive games on Jan. 10th and 12th. ... The Leafs scratched Joey Crabb, Mike Brown and Cody Franson. ... Lane MacDermid, son of former NHL player Paul MacDermid, played his second career game for Boston. ... Grabovski signed a five-year, $27.5 million extension earlier in the day. ... The announced attendance was 19,684.