Germany’s Kerber, the second seed, rallied from a break down in the third set to beat the hard-hitting 10th-seeded Czech 6-3, 4-6, 6-4.
She added the US Open crown to the Australian Open title she claimed in January, breaking Pliskova at love to cap the triumph.
“Amazing to win a second Grand Slam in one year," Kerber said. “It’s the best year of my career.
“It all started for me here in New York five years ago when I reached the semi-finals and now I am here with the trophy," she added. “It’s incredible."
The 28-year-old left-hander, who beat Serena Williams in the final at Melbourne and lost to the US great in the Wimbledon final, will officially rise to world number one on Monday.
But she was assured of that spot when Pliskova toppled Williams in the semi-finals.
“To be number one and win Grand Slam titles was always my dream ever since I was a little girl," Kerber said. “It means so much."
Pliskova, who had never made it past the third round of a Grand Slam in 17 prior attempts, also beat Venus Williams en route to the title match, becoming just the fourth player to beat both Williams sisters in the same Grand Slam.
Pliskova was the first player to take a set off Kerber at Flushing Meadows.
Her powerful groundstrokes had Kerber on the run at times, but her 47 unforced errors were, finally, too much to overcome despite her 40 winners.
When Pliskova’s final forehand sailed out, Kerber was launched on a joyous celebration, climbing into box where coach Torben Beltz was sitting then returning to the court where the tears flowed.
Kerber took advantage of Pliskova’s big-match nerves -- evidenced by a couple of misses at the net -- to break in the opening game.
The quick advantage gave Kerber plenty of breathing room.
She was able to maintain it with authoritative play from the baseline, fending off three break points before cracking Pliskova’s serve again when the Czech double-faulted to give her a set point.
Kerber seized her chance with a forehand down the line to pocket the first frame in 44 minutes, having committed just three unforced errors.
Having saved the first break point she faced in the second set, but unable to make inroads on Pliskova’s serve, Kerber was beginning to look demoralized by the power shots coming her way.
Pliskova, gaining in confidence, grabbed her first break of the match for a 4-3 lead, lofting a lob over the dejected German.
Serving for the set three games later the Czech fired her fourth ace of the match out wide for set point.
Her rocket to the baseline on the next point left Kerber helpless and the match was level at two sets apiece.
“In the second set, I found some power," Pliskova said.
Faced with the challenge, Kerber admitted she was “a little negative" in the second set, but said she drew on the memory of her Australian Open triumph to will herself on, even after conceding the first break of the third set to fall behind 2-1.
Pliskova couldn’t maintain the advantage. Two errors gave a break back to Kerber in the sixth game.
The German was back on top of her game with a hold for 4-3, running for a stinging forehand winner to the corner for game point that fully restored her morale.
“I was trying to stay in the moment," Kerber said. “Trying to play my game."
Even after her capitulation in the final game, Pliskova was looking forward to building on her breakthrough Slam performance.
“It was a great match tonight," Pliskova said. “I knew it was going to be difficult.
“Even though I couldn’t get the win, I’m still happy with the way I played the last three weeks. Hopefully there will be many more finals to come.
“I found out I can play against the best players in the world on the big courts," Pliskova added. “Angie proved she is the number one, it was an honor to play her."