The Saints blew the game open with three unanswered goals in the third term, setting up the 4.6 (30) to 2.4 (16) win at Henson Park in Sydney.
But St Kilda will be sweating on scans to Nicola Barr, who came from the field with a suspected serious knee injury in the last quarter.
Darcy Guttridge and Bianca Jakobsson (ankle) also came off the ground in the final term in a sour end to a successful road trip for the Saints.
It was their fourth win in a row after they had slumped to 1-3 a month ago with consecutive defeats to Melbourne, West Coast and Hawthorn.
Since entering the AFLW in 2020, St Kilda's best result has been ninth (twice) and they have never qualified for finals in six previous seasons.
Dual All-Australian Jaimee Lambert put in a powerhouse performance, showing why she has been one of the best players since the foundation of the AFLW back in 2017.
Lambert, a five-time club best-and-fairest with Collingwood and the Saints, was a constant threat up forward with two goals and 25 disposals.
Midfielder Georgia Patrikios is back to her best after missing all of last season due to injury, gathering 26 possessions and having four clearances.
"You've just got to crack in, try your best every week," she told Fox Footy.
"Hopefully can get into some good form for the important part of the year that's coming up.
"We talk about energy and in that first half we didn't bring that.
"But we came out and put a good third quarter together."
All six goals in the match were kicked to the same end of the ground, although that was more coincidental with wind not appearing to be a major factor.
Young gun Kaitlyn Srhoj enjoyed a breakout game for the Giants, finishing as the leading possession winner on the ground with 27.
GWS slumped to 2-6 with their finals hopes already dead and buried.
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