Bothered by the heat and humidity on an 85-degree night, he nonetheless combined with five relievers on a four-hitter and hit his first major league homer as the Rays beat the Phillies 1-0.
He became the first pitcher from either league to hit a homer that accounted for the only run in an interleague game, something he didn't know until afterward.
"It's one of those funny things you just find yourself a part of sometimes," he said. "I'm going to take pride in that and continue on with my career, and hopefully it's a long one."
Karns, who allowed career highs of seven runs and nine hits while losing 8-3 to Kansas City in his previous start, surrendered three hits in five shutout innings while striking out four and walking two.
"He did it all tonight," manager Kevin Cash said. "Unique win, but we'll take as many as we can get."
Karns said the heat affected him from the outset, to the point that he sweated through two jerseys and a handful of T-shirts.
"It was just hard for me to breathe out there," he said. "It was just one of those days where the heat kind of got to me. ... It was just a battle, from beginning to end."
The Rays, who had lost 10 of their previous 12 games on the road, ended Philadelphia's four-game winning streak and spoiled the major league debut of Aaron Nola, the Phillies' first-round draft pick in June 2014.
Karns' homer, a leadoff shot in the third inning off Nola, represented the first hit by a Rays pitcher in 24 at-bats, dating back to a double by Alex Cobb at St. Louis on July 23, 2014. Including Karns' 1-for-2 effort Tuesday, Tampa Bay pitchers are now 1-for-16 this season.
Nola, last year's seventh overall pick, was the first Phillies player to debut the year after he was drafted since another pitcher, Pat Combs, did so in 1989. Nola went six innings and allowed one run and five hits, while striking out six and walking one.
"He was good," Cash said. "It looked like he had a lot of deception, a lot of life on his fastball. ... For a young pitcher he looked incredibly polished. Threw all his pitches over the plate. Definitely kept us off-balance."
Nola, who combined to go 10-4 while pitching at Double-A and Triple-A this season, threw 88 pitches, including 59 strikes.
"It was pretty awesome to be out there, feel the energy of the fans and pitch at this level," he said. "It was amazing."
Nola (0-1) also picked up his first major-league hit, a fifth-inning single off Karns.
Karns hit Nola's first pitch of the third, a fastball, into the seats in left-center to account for the game's only run.
Karns also became the first AL pitcher to homer since Baltimore's Zach Britton did so against Atlanta on July 3, 2011, and the first pitcher from either league to homer in a 1-0 game since Milwaukee's Yovani Gallardo did so against Pittsburgh on April 29, 2009.
"I really wasn't sure if it was going out," Karns said. "I was really kind of caught off (guard) that I even hit it. I took off, and it just kept going. ... I would like to say I meant to do that, but it was just one of those things: I was just trying to put the ball in play, and I had a great result."
Karns said he asked Cash before he batted if he should take a strike before swinging, but Cash told him to hack at the first good offering he saw.
"Some of us saw him take batting practice in Toronto (over the weekend)," Cash said. "He kind of put on a show. You don't anticipate that he's going to hit a home run. Pretty exciting. When the ball left the bat, I think all of us thought it had a chance."
NOTES: Phillies 3B Maikel Franco did not play after an injured right elbow led to his removal in the late innings of Monday's 5-3 win over the Rays. Interim manager Pete Mackanin said the injury did not require an MRI and that Franco is day to day. ... Mackanin also said RHP Jerome Williams, activated from the disabled list on Monday, will start Friday against the Chicago Cubs in Wrigley Field. Mackanin had said Monday that Williams would work out of the bullpen, but he amended that Tuesday, saying Williams will be available in relief only in an emergency until his start. "I probably confused a lot of people," Mackanin said, "but I was a little confused myself, with everything that happened last night." ... The Rays activated RF Steve Souza Jr. from the disabled list and optioned OF Grady Sizemore to Triple-A Durham. Souza, whose 15 homers lead the Rays, struck out four times in as many at-bats Tuesday, the first three times against Nola.