The clubs will be completing a four-game season series that began with a two-game split in San Francisco in April.
San Francisco Bay Area product Mitch Haniger had a two-run single in a four-run first inning in a 6-4 Mariners win in the first meeting, before the Giants bombed Felix Hernandez in the rematch the next day, with Gorkys Hernandez, Brandon Belt, Pablo Sandoval and Brandon Crawford smacking home runs.
Neither Giants rookie Andrew Suarez (3-6, 3.94 ERA) nor Mariners standout James Paxton (8-4, 3.70) pitched in that series, nor has either ever faced Tuesday's opponent, but each has dabbled in interleague play this season without much success.
Suarez's last start was a 6-2 home loss to the rival Oakland Athletics in an interleague game the day before the All-Star break. He was roughed up by the A's for four runs in five innings.
The 25-year-old made one other interleague start this season, against Houston, and that went even worse. He is 0-2 with a 9.00 ERA in those two starts.
The Giants will be playing their seventh consecutive game against American League competition, having gone 2-4 in two sets of three-game series with the A's.
San Francisco didn't take full advantage of having an extra hitter in the lineup their past three games in Oakland, with Nick Hundley, Hunter Pence and Buster Posey combining to go 3-for-12 (.250) with a double, two RBIs and five strikeouts.
Most of that damage was done by Pence, who had three hits, including a game-tying double with two outs in the ninth inning, in Saturday's 4-3, 11-inning defeat.
Pence, a career-long National Leaguer, has hit .308 as a DH in his career.
Andrew McCutchen is the only active member of the Giants' roster who has ever gotten a hit off the Mariners' Paxton, in a 2016 game for Pittsburgh.
Paxton is expected to be reinstated from the disabled list before the game, having experienced back pain in the first inning of his last start July 12 against the Los Angeles Angels.
His only interleague outing this season came in his previous start, a 5-1 loss to Colorado.
The 29-year-old told reporters last week that he's fully healthy and looking forward to Tuesday's return.
"Everything all good," he reported of a 40-pitch bullpen session. "Let some rip, no problems. Was able to get through my pitches, finish them off, so it was definitely good."
The Mariners struggled in their interleague series last week at Colorado, losing all three games. They take a 2-6 interleague record into the game. The Giants haven't fared much better, going 5-8.
Haniger, who played at Archbishop Mitty High in San Jose, reached base in four of nine plate appearances with two singles and two walks in the earlier series in San Francisco.
He had been 0-for-8 with a walk in nine previous plate appearances against the Giants as a member of the Arizona Diamondbacks in 2016.
He's hitting .297 against left-handed pitchers this season.