Coming into the Miami Open a week ago, the American's sole victory on the ATP World Tour in 2018 had come against Moldovan world No. 94 Radu Albot.
Nine days later at Crandon Park, the towering 6-feet-10-inch Isner had beaten several of the world's top players to lift the trophy in Miami, his first ever Masters 1000 victory.
Among his scalps were Juan Martin del Potro, the Tour's in-form player who Isner dispatched expertly in the semifinal, world No. 3 Marin Cilic and, in the final, world No. 4 Alex Zverev.
"I couldn't have scripted this," Isner told reporters after his match. "I came into this tournament, I had won one ATP match all year and was playing very poorly."
"I won my first match in three sets and that's how tennis goes -- you start to gain a little confidence and next thing you know things start to roll your way."
Isner started his campaign in Miami with an up and down three-set win over Jiri Vesely, but then didn't drop another set until losing the first on a tiebreak to Zverev in the final.
The North Carolina native had three times made it to the final of Masters 1000 events, in 2012, 2013 and 2016, but had never walked away with the title.
"You can't replicate moments like this," Isner told the crowd during the trophy presentation. "I'm toward the latter part of my career, this is the best moment of my career.
"I was just ready for this moment. I've been here three other times, and I've lost three times on this stage. I was just ready for it."
Only Andre Agassi and Roger Federer have taken Masters 1000 titles at an older age.
The win sees Isner pocket $1,340,860 and climb eight places to No. 9 in the world, matching his career-high ranking.
USA clean sweep
Sloane Stephens' victory in the women's final against Jelena Ostapenko a day earlier means it was an American clean sweep in Miami.
It was the first time since 2004, when Andy Roddick and Serena Williams were crowned champions, that a US pair has won both the men and women's singles draw.
Stephens, who won her first major at the 2017 US Open, impressively battled her way past four grand slam winners -- Garbine Muguruza, Angelique Kerber, Victoria Azarenka and, in the final, Ostapenko -- to win her maiden title in Miami.
Reigning French Open champion Ostapenko hadn't dropped a set or lost a tiebreak all fortnight, but both streaks were abruptly ended as Stephens triumphed 7-6(5), 6-1.
"This place is pretty special to me," the Floridian told reporters. "I grew up playing tennis here."
Following victory in the US Open at the end of last year, Stephens sunk to eight straight defeats but her Masters 1000 triumph, the sixth WTA title of her career, sees her break into the world's top 10 for the first time.