Texas topped Chicago's John Danks on Opening Day and Seattle's Blake Beavan on Tuesday.
Millwood was the Rangers' Opening Day starter from 2006-09. He won 48 games with Texas in his four seasons with the club.
"I enjoyed my time here," Millwood said. "There's not a huge difference in the guys over there. It's still pretty much the same team. But it's just another game, really."
The Rangers last faced Millwood on Aug. 22, 2010, when he was pitching for the Orioles. He allowed six runs in six innings in that contest, which Texas won, 6-4.
"Whether it's a guy you know or have played with or don't know, you're still trying to do the same thing," outfielder David Murphy said. "It might be an advantage having watched him work over a few seasons, what he's got and how he pitches."
The Mariners added Millwood during the offseason to serve as a possible veteran presence for their young rotation. Ace Felix Hernandez is just 26 and Hector Noesi and Blake Beavan are 25 and 23, respectively. Millwood turned 37 in December.
Millwood won a spot in the rotation after posting a 3-1 record and 2.57 ERA during Spring Training.
For the Rangers, right-hander Colby Lewis makes his second start of the season. He held the White Sox to two runs over six innings, striking out nine with one walk in a 3-2 victory on Opening Day.
Mariners: Ryan to return to lineup on Wednesday
Manager Eric Wedge said he benched shortstop Brendan Ryan on Tuesday for "accountability" reasons. Wedge said the 30-year-old will be back in the lineup on Wednesday.
"When I talk about certain things that need to happen this year -- and there are conversations that have been had -- there's a level of accountability and responsibility that everybody has," Wedge said. "It's no more or less than that. I'm not going to dive in to details on it. I'll leave it at that."
In 61 career starts at Rangers Ballpark in Arlington, Millwood is 28-17 with a 4.56 ERA, a tad higher than his career ERA of 4.10.
Still, Millwood said that despite the venue being known as a hitters' park, he carries the same mentality to the mound that he would in any other ballpark.
"It's like everywhere else," Millwood said. "You try to keep the ball down. ... You just try to make good pitches. If you can keep the ball on the ground here, you've got a chance."
Rangers: Kinsler signs through 2017
The Rangers could hold a press conference Wednesday to officially announce second baseman Ian Kinsler's new five-year, $75 million contract.
Kinsler took a physical on Tuesday. His deal will keep him in Texas through 2017, with a club option for 2018.
"I'm really happy for him; he's one of the best second basemen in the league," outfielder Nelson Cruz said. "I couldn't be happier."
In the first start of his Major League career, Neftali Feliz tossed seven shutout innings. He gave up just four hits and two walks while striking out four in the Rangers' 1-0 on Tuesday.
Feliz made 154 appearances out of the bullpen the last three years for Texas. He was the club's full-time closer the last two seasons, as he compiled 72 saves.
Hernandez will start the Mariners' home opener on Friday against the Athletics.
Rangers pitcher Yoshinori Tateyama, who is on the 15-day disabled list with stiffness in his lower back, will begin a rehab assignment with Triple-A Round Rock on Wednesday.