Victor Hedman had a goal and an assist, and Ross Colton scored the game-winning goal at 5:32 of the third period for the Lightning (21-6-2), who are 5-0-1 against the Blackhawks this season.
"He is playing phenomenal," Tampa Bay forward Yanni Gourde said of Colton, a forward who played his fifth NHL game. "He's works really hard. He makes the simple plays, he finishes his hits, wins draws … he does it all. It's very fun to watch."
Mattias Janmark had a goal and an assist, and Dylan Strome scored in his return after missing 11 games for the Blackhawks (14-12-5) while in NHL concussion protocol. Kevin Lankinen made 19 saves in Chicago's third straight loss.
"It was nice to get back out there with the guys, I'm feeling a lot better," said Strome, who last played Feb. 19. "We did a lot of skating while I was out, got back to skating, so the legs felt good tonight, but unfortunately we couldn't get the win."
The teams will finish the two-game set here Saturday.
Colton received a pass from Mathieu Joseph as he got behind the Blackhawks defense and beat Lankinen with a backhand to make it 3-2.
"[Our line] tries to play a gritty type of game," Colton said. "[Pat Maroon] is so effective below the circles, and [Joseph] has unbelievable speed. I think I am pretty effective down low as well. We're going to get offensive-zone time with Joseph's speed. It's not always about scoring, it's about creating momentum for the other lines."
Hedman scored into an empty net with 16 seconds remaining for the 4-2 final.
"All four lines played good tonight," Gourde said. "When we're making the simple plays -- chipping the puck in and working down low -- you just have to play smart, and we did that in the third period after we got the lead."