Having used a protective ranking through relatively recent changes regarding pregnancy on the WTA Tour, the Bulgarian was aiming to continue her fairytale comeback in New York, after her initial retirement from the sport three years ago.
Pironkova played a masterclass of a first set, as her strong serve and low unforced error count startled Serena and threatened a huge upset.
The youngest of the Williams sisters showed her fight and the champion qualities we have all known to associate her with as she battled hard to take the second set.
Pironkova began to wane as the match wore on as Serena accelerated away to seal her place in another US Open semi-final.
Both players started off the match brightly as the 38-year-old American powered down three aces in her opening service game. A sublime lob from Pironkova showed Serena this contest would not be as straight-forward as first seemed.
For those unfamiliar with the 32-year-old Bulgarian's gameplay, she moves quickly around the court, serves big and possesses power off both wings.
She too held serve in the early exchanges as a volleyed drive from Williams hit the net and bounced over, but for Pironkova to push a slapped forehand onto the tape, before fortuitously bouncing over to square the opening set at one game all.
Both players continued to hold their serve until the pivotal moment came in the fifth game of the first set, as Pironkova secured the first break of serve of the match.
At 30-15, Serena looked like holding comfortably until a forehand winner from Pironkova dipped into the corner for 30-all.
A double fault from Williams brought up the Bulgarian's first break point of the match. However, an ace down the tee saved Serena, albeit briefly.
A sublime backhand winner from Pironkova gave her the break to put her 3-2 ahead of the six-time champion.
Pironkova backed up the break with a very focused service game to move further ahead.
At 5-3, a fabulous lobbed backhand from Pironkova threw up set point only for the American to save double set points and preserve a hold of serve.
However, Pironkova was not to be denied as she served out a well deserved, efficient opening set.
The Bulgarian began the second with the same high energy as mistakes from the Williams racquet gifted her another break of serve.
In one of the crucial junctures of the match, Serena showed her steel to break back at one game apiece with powerful hitting off the forehand and backhand sides.
A rasping forehand winner put Williams 30-0 up and she looked to be cruising towards an easy hold. However, sloppy errors let Pironkova back into the game to eventually take it to deuce.
Two thumping aces from Serena helped her hold serve to go 2-1 up.
The set continued on serve, until Serena earned triple break points against the Bulgarian's almost impenetrable serve. A smart put away volley from Pironkova saved the first until the rally of the match, a 26-shot marathon went the way of Serena as she slapped a forehand out wide that Pironkova could only dump a drop shot into the net.
Serena would go on to clinch the set 6-3 with an ace down the tee, three in total for the service game to level the match.
The final set started with the same intensity as the drama continued to unfold. The game went to a fifth deuce, the longest of the match with both players looking physically exhausted.
This included the Bulgarian saving two break points but also blowing two vital game points that would have put her ahead again in the match.
But it was Williams who finally broke the gridlock as she seized her chance at the third time of asking as Pironkova went long.
Serena backed up the break with another hold and never looked back as she secured another break to move 5-2 up before converting the first of her triple match points, putting away a classy forehand volley to wrap up a highly impressive victory.
A re-match of the 2018 Naomi Osaka vs Williams final now looks increasingly likely, but the winner of Victoria Azarenka and Elise Mertens will certainly have a say about that.