The loss left the Titans in danger of missing the finals, with Parramatta keeping alive a chance of taking their spot by beating Wests Tigers 38-4 in Sunday's later game.
NSW State of Origin star Southwell scored the Knights' first and last tries – the second with 40 seconds left on the clock – to end her side's three-match losing streak.
In a gritty battle as the Titans tried in vain to nail down a top-six spot, the lead changed three times in the first half before Newcastle edged ahead 16-12 at the break through a Sienna Yeo crash play under the posts.
Debutant Fane Finau scored early for the Knights but two quick tries for Estanoa Faitlala-Mariner and 18-year-old centre Phoenix-Raine Hippi locked the score at 22-22 with 10 minutes to play.
A Lauren Brown field goal attempt sailed just to the left in the 67th minute as the Titans scrambled for the win.
But up came Southwell with a dummy and a step in the 69th to race over for the match-winner. The 20-year-old had not scored a try since round eight of 2023, but snared two in this match along with four goals.
Newcastle ended the game safe in fifth spot. Gold Coast remain sixth, but without yet sealing that spot and finals football.
Parramatta's finals chances still have some oxygen after their win over Wests Tigers in the last game of round 10 moved them to seventh.
The Eels now play the Bulldogs next Friday at CommBank Stadium.
If they win and the Titans lose to Canberra, Parramatta will be playing finals for the first time since 2022 when they went all the way to the grand final.
On Sunday night against the Tigers they showed they had plenty of points in them.
Captain and second rower Mahalia Murphy scored a hat-trick and winger Martha Mataele a double in the seven tries posted by the Eels. Halfback and goalkicker Rachael Pearson was landing them from both sidelines in her five conversions.
Gold Coast will have to face the Raiders without their leading try scorer, winger Georgia Grey, who failed her concussion test early in the opening minutes on Sunday against Newcastle.
The earlier game in Hamilton, New Zealand, brought together the two highest try scorers of the season (13 each) in Payton Takimoana (Warriors) and Tamika Upton (Brisbane).
But with Upton's double in the first half highlighting the Broncos' 26-6 win, she's now out on her own.
For a club averaging 36 points per game, the Broncos were bang on target with an 18-0 halftime lead.
The visitors looked in control but things could have got interesting in the Warriors' last home game of the season. They had players held up over the line three times and had a try disallowed by the bunker.
Two second-half tries to Mele Hufunga and Lauren Dam stretched the Broncos' lead to beyond the Warriors grasp.
In a nod to Upton's workload, she was taken off early by coach Scott Prince with one eye on the Broncos' clash with the in-form North Queensland next weekend.
"We looked at this game as a really good challenge to prepare us for the future games and it certainly gave us that," Prince said.
"We spoke about how strong their forward back would be. So for us moving towards the finals we needed to be challenged in the middle and the Warriors did that.
"We managed to repel a few sets on our line and that was impressive.
"Scoring points is one thing, and we've got a good attacking team but if you want to win a premiership, defence has to be the focus."
The Warriors travel to Campbelltown to face Wests Tigers but may be in danger of losing influential No.6 Patricia Maliepo, who limped from the field in the 56th minute after her right leg was caught under a Hufanga tackle.
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