Ryan Flaherty also homered and had a career-high three hits for the Orioles, who never trailed but had to withstand four homers by Seattle.
McLouth connected off Brandon Maurer to make it 11-6 in the sixth, and that was enough offense to fend off the Mariners, who closed the gap in the eighth with solo shots from Kendrys Morales and Michael Morse.
Jim Johnson worked the ninth to earn his 38th save and secure the victory for Chris Tillman (14-3).
Davis drove a pitch from Aaron Harang (5-10) over the right-field wall and onto Eutaw Street to give Baltimore a 5-3 lead in the third inning. The solo homer traveled an estimated 442 feet and gave Davis a major-league high 101 RBIs.
He is the fifth Oriole to hit 40 homers in a season, joining Brady Anderson (50), Frank Robinson (49), Jim Gentile (46) and Rafael Palmeiro (43).
Adam Jones had three RBIs for Baltimore, which has won 10 of its past 12 against Seattle.
Tillman gave up a season high-tying six runs, as well as eight hits and three walks. But the right-hander improved to 5-0 in five career starts against the team that traded him along with Jones to the Orioles in 2008.
Morales went 4 for 4 and has 13 hits in his past 17 at-bats. Michael Saunders and Humberto Quintero also homered for the Mariners, who have dropped four in a row and six of eight.
Harang allowed seven runs and seven hits in five innings.
On Thursday night, the Mariners allowed six runs in the bottom of the ninth in an 8-7 loss to Boston. Acting manager Robby Thompson addressed his young team before this game to make sure there would be no carry-over.
"It's over and done with," Thompson said. "I want to make sure we forget about it ... and move forward."
They didn't. After going down in order with two strikeouts in the top of the first inning, Seattle promptly fell into a 4-0 hole.
McLouth singled and Harang issued two straight walks before Jones doubled in two runs, and another scored when left fielder Raul Ibanez mishandled the hit. Matt Wieters capped the uprising with a sacrifice fly.
Seattle used three walks, a two-run homer by Saunders and an RBI single by Morales to close to 4-3 in the third.
After Davis homered in the third and Flaherty hit one in the fourth, Quintero connected leading off the fifth.
Jones hit an RBI single in the bottom half for a 7-4 lead, but the Mariners got two runs in the sixth on a run-scoring double by Michael Morse and a sacrifice fly by Saunders.
NOTES: The Orioles placed 2B Brian Roberts on paternity leave as he awaits the birth of his first son. Baltimore filled out the roster by activating RHP Steve Johnson (strained oblique) from the disabled list. ... Seattle 2B Nick Franklin went 0 for 5 and is hitless in his past 17 at-bats. ... Roberto Alomar was inducted into the Orioles Hall of Fame before the game. ... Wieters went 0 for 3 and is hitless in his past 25 at-bats, the longest drought of his career.