Porcello (12-2, 3.47 ERA) is 9-0 at home this season, and the Red Sox are unbeaten in the 10 starts he has made at Fenway. In those 10 starts, he boasts a 2.98 ERA with 52 strikeouts.
He earned his fourth consecutive win in his last start, holding the National League West-leading San Francisco scoreless on four hits and two walks with three strikeouts in 6 1/3 innings at Fenway.
"Rick is just in a very comfortable place in this ballpark," Red Sox manager John Farrell said about Porcello, who hasn't lost since May 17 at Kansas City.
Minnesota (37-60) won its second straight game Saturday, pounding out a season-high 19 hits to beat Boston in a 11-9 shootout.
The Twins lost a 13-2 laugher in the series opener before using a prolific pitching performance from Kyle Gibson to notch a 2-1 victory Friday.
The Red Sox (54-41), meanwhile, fell 1 1/2 games behind Baltimore for first place in the American League East after the Orioles earned a 5-2 victory over Cleveland on Saturday.
Porcello, who spent six seasons with Detroit, has plenty of experience facing the American League Central-worst Twins.
The right-hander is 8-9 with a 3.87 ERA in 26 career starts against Minnesota -- his most against any opponent.
He has already faced the Twins once this season, allowing four runs (one earned), five hits and two walks with five strikeouts in a seven-inning no-decision June 12.
Tommy Milone (3-2, 4.71 ERA) is winless in three career starts at Fenway, going 0-2 with a 9.88 ERA.
The southpaw's last against the Red Sox was one of his best, giving up two earned runs and four total on nine hits and a walk over five innings in a no-decision last June 4 at Fenway.
Milone is 0-2 lifetime with a 9.64 ERA in four starts against Boston.
On Tuesday, he allowed two runs on four hits and two walks with four strikeouts over a season-high 8 1/3 innings in a victory against the Tigers.
"It feels good to go deep in the game," Milone said. "I just wanted to make sure I attacked the zone. I felt like I was able to do that pretty much all night."