Sabalenka ruthlessly attacked Anisimova's shaky service game to complete a 6-3, 7-6(3) victory on Arthur Ashe Stadium, which cements her status at the pinnacle of women's tennis.
The 27-year-old from Belarus had gone into Saturday's final knowing it was her last chance to grab a Grand Slam crown in 2025 after agonising losses in the Australian and French Open finals.
Sabalenka duly atoned for those defeats to end Anisimova's hopes of a remarkable redemption just two months after her traumatic 6-0, 6-0 thrashing by Iga Swiatek in the Wimbledon final.
"It's crazy, all those tough lessons were worth it for this one," said Sabalenka after becoming the first woman to successfully defend the US Open since Serena Williams in 2014. "I'm speechless right now."
Anisimova had won six of nine previous encounters against Sabalenka, a run which included a victory in the semi-finals at Wimbledon.
But a determined Sabalenka, playing in the seventh Grand Slam title game of her career, brought all her experience to bear as she slammed the door on Anisimova's dream of a maiden Grand Slam title.
"Losing in two finals in a row is great, but it's also super hard," Anisimova said.
"I think I didn't fight hard enough for my dreams today," revealing that the lighting under the arena's closed roof had made it difficult to serve.
"There was no way of adjusting, because I could not see the ball when I was serving, and that was a huge shock to my system," she said.
Sabalenka clinched victory after once again demonstrating her incredible prowess in tiebreaks - winning her 19th consecutive breaker 7/3 to clinch in one hour and 34 minutes.
Anisimova, meanwhile, was left ruing her inability to make the most of break points at key moments, in sharp contrast to Sabalenka, who converted five of her six break point chances.
That imbalance was on display early in the first set, when Anisimova failed to convert three break-point opportunities as Sabalenka took a 2-0 lead.
Yet Anisimova hit back in the third game, lasering a backhand winner into the corner to earn a break point before unfurling a rasping forehand winner to break back before holding for 2-2.
With the momentum behind her and her groundstrokes forcing Sabalenka around the court, Anisimova then broke again for a 3-2 lead.
But that was the catalyst for Sabalenka to raise her game, and she broke to love before holding to edge back in front.
Anisimova's faltering serve again betrayed her in the eighth game, the eighth seed double-faulting twice in quick succession to hand Sabalenka two break points at 15-40.
Sabalenka needed no further encouragement, and she duly converted before holding to take the first set.
Sabalenka punished another wayward service game from Anisimova early in the second set and looked in complete control at 3-1.
Yet Anisimova wasn't quite finished, and she held confidently before breaking back to love to level it at 3-3.
The fightback was short-lived, however, and when Anisimova thumped a wide-open forehand long to gift Sabalenka a 15-40 lead, the Belarusian once again seized her chance for a break.
Sabalenka held for 5-3 and was soon serving for the match at 5-4. Yet she allowed Anisimova off the hook after ploughing a wide-open smash into the net.
Instead of giving her match point, Anisimova had break point, which she took to give her a lifeline.
But in the tiebreak, Sabalenka reasserted her control, and she sprinted into a 6-1 lead before closing out victory.