The Red Sox enter the set having dropped four consecutive games, which already exceeds their longest losing streak of last season -- when they won a world championship under first-year manager John Farrell.
Boston has sunk to fourth place in the five-team American League East Division, though it's just three games behind the first-place New York Yankees and only a game out of third place, which is currently occupied by the Blue Jays.
Toronto has won five of its last seven.
The Red Sox have hit just .189 in the four-game slide and the starting pitchers have compiled an unsightly 5.73 earned run average across the last six games. They did score 16 runs in a three-game series with Toronto at Rogers Centre in late April, however, and will return to the road for 24 of the next 36 games after this series.
The Blue Jays start lefty J.A. Happ for the fourth time this season after he'd opened on the disabled list and then went to the bullpen.
He last started on Thursday and threw six innings of one-run ball in a 4-2 defeat of Cleveland.
"You're always (showing something) to somebody," Happ said. "I felt good, definitely nice to go out there and have a fairly strong outing."
Happ has never started at Fenway Park, but he's faced the Red Sox four times and is 1-2 with a 5.06 ERA.
Happ will be opposed by fellow southpaw Felix Doubront, who defeated Minnesota on Wednesday for his first victory since April 3.
He gave up a single run in 6 1/3 innings against the Twins and has surrendered just two runs in 11 2/3 innings after a five-start skid that yielded no wins, three losses and an ERA near 6.
Doubront faced the visiting Blue Jays twice in 2013 at Fenway and was 1-0 with a 2.70 ERA.
On Sunday in Texas, Mitch Moreland's two-run home run helped the Texas Rangers to a 6-2 win over the Blue Jays in the finale of a three-game set.
Edwin Encarnacion and Juan Francisco hit solo homers for the Blue Jays.
R.A. Dickey (4-4) lost for the first time in six starts as he was touched for four runs on three hits with three walks in 6 1/3 innings.
"We're definitely going in the right direction but there's more there," Dickey said. "I think we all know it. Today's a game we probably should have won."
In Boston, Victor Martinez hit a two-run home run and the Detroit Tigers polished off a three-game sweep of the Red Sox with a 6-2 win.
Xander Bogaerts finished 2-for-4 with an RBI for the Red Sox.
Jake Peavy (1-2) allowed five runs on 11 hits over six innings.
Boston took two of three from the Jays earlier in the year.