The 28-year-old came in 02:15.3 faster than Heidi Weng who took silver for Norway, ahead of Nadja Kaelin of Switzerland, who sealed the bronze medal.
Crashes from Andersson had cost Sweden gold in the 4x 7.5km relay and prevented the Swedes from taking every women's cross-country gold on offer at Milan-Cortina. That was the third silver of these games for Andersson, who was runner-up in both the 10km freestyle and 20km skiathlon.
With two of her teammates, Frida Karlsson and Jonna Sundling, out of the 50km with illness, hopes were resting on Andersson's shoulders to redeem herself and take her first individual Olympic title.
If there was any pressure on the 28-year-old, she didn't show it, leading at every checkpoint, as she led a group of four that was beginning to pull clear, though Weng, Austria's Teresa Stadlober and Jessie Diggins of the USA were sure to provide stiff competition.
However, a crash from Diggins around 8km put her on the backfoot, before the Swede and Norwegian began to pull away from Stadlober.
At the halfway mark, the leading pair had an advantage of 01:45 over Stadlober, who was being chased hard by Kerttu Niskanen of Finland, Norwegian Kristin Austgulen Fosnaes and a recovering Diggins in the race for bronze.
It looked like a terrible case of deja vu for Andersson, when she fell immediately after she and Weng changed their skis at the 28.8km mark, but the stumble did not hold her back for long, and with the fresh skis, Andersson took the opportunity to attack.
Pushing hard, the Hudiksvall native opened up a 10-second gap with 20km to go, and continued determined skiing allowed Andersson to increase that to 30 seconds with 36km gone.
The Swede didn't let up, and began the last of the 7km laps 01:13 clear of Weng, and only disaster would prevent them from coming home first and second, as Weng was over three-and-a-half minutes ahead of the group of five gearing up for a heated battle for bronze, including Switzerland's Kaelin.
A fast finish from Eliza Rucka-Michalek saw her make it a six-skier fight for the final medal, but in the meantime, Andersson was powering up the final hill to receive a fantastic reception and win gold in a time of 2:16:28.2.
Weng finished in second place to complete her games with one gold, one silver and one bronze, and one the final climb, Kaelin was the smoothest, putting enough of a gap between herself and the rest of the group to take bronze for Switzerland.
Fosnaes of Norway came in an agonising fourth place, as Diggins completed the top five.
A six-time world champion, Andersson has finally added an Olympic gold to the three silvers she had already won in 2026, plus a bronze from Beijing 2022 and another silver at Pyeongchang 2018.
Sweden finish with five golds, four silvers and one bronze from the six women's cross-country events at the 2026 Winter Olympics.
