Oklahoma City had been rocked after suffering a slew of injuries followed by back-to-back 20-point defeats heading into Monday's showdown with last season's Eastern Conference finalists.
But a sublime performance from two-time reigning NBA Most Valuable Player Gilgeous-Alexander carried the Thunder to a morale-boosting win at Cleveland's Rocket Arena.
Gilgeous-Alexander's 43-point haul came from 14-of-35 shooting from the field with four three-pointers and eight assists.
Oklahoma City, missing three starters in Chet Holmgren, Jalen Williams and Cason Wallace, were also boosted by 20 points from Ajay Mitchell and 12 points from Kenrich Williams.
Cleveland's points were spread through the line-up, with seven players reaching double figures, including Donovan Mitchell and Meleek Thomas with 17 points apiece.
"You never know what the future has in store for you, and all you can do is play the cards you're dealt, that's what we try to do," Gilgeous-Alexander said of the Thunder's response to their injury crisis.
"Whatever the game needs we try to play to the best of our ability and come out with a W (win). And tonight we did that."
Oklahoma City's victory, which lifts the Thunder to 4-2, launched a packed slate of Monday fixtures across the NBA as the league prepares to take a rest day on Tuesday due to the US mid-term elections.
The league's last unbeaten record fell as the Memphis Grizzlies were upset 135-134 at home by the New Orleans Pelicans.
Ty Jerome sparked a thrilling late fightback for Memphis with 15 points in the fourth quarter to send the game to overtime, but the Grizzlies' rally fell just short.
The Philadelphia 76ers improved to 7-1 to stay on top of the Eastern Conference with a 126-107 defeat of the Chicago Bulls.
Tyrese Maxey scored 26 points and Jaylen Brown added 25 to guide the Sixers to a fourth consecutive win.
V.J. Edgecombe scored 21 points and LeBron James and Joel Embiid added 15 points each.
The reigning NBA champion New York Knicks improved to 3-4 with a 103-90 defeat of the Brooklyn Nets at Madison Square Garden.
Landry Shamet led the Knicks scoring with 22 points off the bench while Jalen Brunson added 19 points, including four three-pointers.
Around the league
Cade Cunningham's 33-point display helped the Detroit Pistons move to 6-1 with a 124-91 drubbing of the Charlotte Hornets.
The Washington Wizards pulled clear of the Orlando Magic 103-94 on the road.
The Atlanta Hawks are at 4-4 after a 108-104 defeat of the Indiana Pacers.
With Darius Acuff Jr. leading the Kings in scoring with 25, the team pulled off their first victory of the campaign as they move to 1-6 on the season and 1-4 on the road as they took down the Dallas Mavericks 115-100.
One team that stayed red-hot however, was the Houston Rockets, moving to 7-1 on the season behind 26-7-10 from Alperen Sengun as they took down the Boston Celtics 109-93, who saw another great performance from Jayson Tatum.
The same can't be said for the Milwaukee Bucks who drop to 1-6 on the season despite 21 points from Tyler Herro, with another stellar Lamelo Ball performance leading a 112-100 Timberwolves win in the absence of Anthony Edwards.
It's much of the same for the Utah Jazz who also fall to 1-6, with 22 from Lauri Markkanen not enough to save the day as 21-7-8 from Dylan Harper was enough for the San Antonio Spurs to cruise to the 119-97 win.
Then, there's the surprise start of the now 5-1 Portland Trail Blazers, with Deni Avdija and Damian Lillard combining for 48 on the night as Jamal Murray posted 35 points in the 118-110 defeat as the Denver Nuggets fall to 3-3 on the year thus far.