Iwakuma (9-5) improved to 9-0 in his last 14 road starts, the second-longest such streak in club history. He is 5-0 outside Seattle this season.
Dustin Ackley hit a two-run double in Seattle's four-run fourth against Trevor Bauer (4-6). Mike Zunino homered in the fifth for the Mariners, one of six teams scrapping for the AL's second wild-card spot.
The Indians are 5-7 since the All-Star break and are trying to decide whether to be active before Thursday's trade deadline.
Once again, Iwakuma didn't do anything to hurt himself. He allowed two runs and six hits, and only walked one his first free pass in six starts. The right-hander has walked just nine all season.
Fernando Rodney pitched the ninth for his league-leading 29th save.
The Mariners, who came in with the fewest runs scored in the AL, took a 4-0 lead in the fourth when they hit three doubles off Bauer.
Kyle Seager opened the inning by bunting against the shift, pushing a ball down the third-base line. Bauer hit Zunino, and one out later, Corey Hart hit an RBI double. With two outs, Ackley ripped his double off the right-field wall to make it 3-0.
Chris Taylor added another RBI double just over the glove of leaping left fielder Chris Dickerson.
Zunino's 16th homer gave the Mariners a 5-0 lead in the fifth and chased Bauer, who had gone at least six innings in each of his previous four starts.
Iwakuma dominated the Indians through four, but Cleveland got two runs in the fifth on an RBI single by Yan Gomes and Jason Kipnis' run-scoring groundout.
Mariners: Left-hander James Paxton (strained back muscle) will throw a bullpen session Wednesday, and as long as there are no setbacks, he could start Saturday in Baltimore. He hasn't pitched in the majors since April 8.
Indians: As center fielder Michael Bourn rehabs his surgically repaired left hamstring, manager Terry Francona is trying to let the speedster recover at his own pace. Bourn has been on the disabled list since July 6, and it's not yet known when he will go on a rehab assignment or be activated. Bourn took batting practice before Tuesday's game.
Two of the AL's top pitchers match up in the second game of the series when Seattle's Felix Hernandez takes on Cleveland's Corey Kluber. Hernandez (11-2) has allowed two runs or less and pitched at least seven innings in 13 consecutive starts, an AL record. King Felix, though, is just 7-5 in his career against the Indians, with all five losses coming in Cleveland.
Kluber (10-6) carried a perfect game into the seventh inning of his previous start.