Before a home crowd of over 17,000, the defending premiers clawed back from 16-4 down to level the scores with back-to-back tries as the final 10 minutes approached on Sunday.
But when the Broncos again kicked clear through Lauren Dam with eight minutes remaining, Newcastle were on the back foot once more.
Brisbane's goal-line defence had been the difference between the sides all day, repelling the Knights' repeated advances to begin the second half.
So when Brisbane held powerful forward Caitlan Johnston up in the final minutes, the Knights looked as though their chances were running out.
But that was before fullback Tamika Upton, the Knights' most threatening player all afternoon, spread the ball right to Shanice Parker, who completed a try-scoring double.
The ensuing conversion attempt was no sitter for Southwell.
But from halfway between the touchline and the centre of the goal-posts, the 18-year-old piloted the ball over the black dot to seal a famous Newcastle win.
The victory means the Knights have won their last five games at McDonald Jones Stadium, a streak that stretches back to the 2021 season.
The triple premiership-winning Broncos, meanwhile, are yet to break into the top four as the NRLW season passes its halfway point.
Brisbane started the campaign with back-to-back losses that have left them playing catch-up.
They'll have to be at their best against red-hot newcomers Canberra to get their finals tilt back on track next week.
The Knights, meanwhile, have won four from five games and finish the weekend entrenched in the top four.
The Knights lost premiership-winning prop Simone Karpani to a leg injury that she suffered making a tackle late in the first half.
Rookie Broncos winger Ashleigh Werner joined her in the casualty ward, concussed by Parker's elbow as she made a try-saving tackle before half-time.
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