The England international produced two superb second-half saves from Southampton forward Che Adams as the Magpies secured a vital 1-0 win from a breathless Carabao Cup semi-final first leg at St Mary's.
Joelinton set aside a disallowed goal and a shocking miss to claim the visitors' 73rd-minute winner, while Saints substitute Adam Armstrong had a leveller ruled out for handball following VAR intervention.
Newcastle manager Eddie Howe, who warned there is still a long way to go in the tie ahead of next week's return meeting, saluted the impact of his in-form keeper, while Magpies midfielder Bruno Guimaraes went a step further.
"One goal is important, we could score more but most important was to be one goal in front of Southampton," the Brazilian midfielder told Sky Sports.
"I want to thank Nick Pope, I think he's the best goalkeeper in the world. Let's keep it going."
Speaking of a player he signed from Burnley in the summer, Howe said: "Nick made some big saves today, especially the first one from Adams (which) I thought was a big moment in the match.
"He stood up tall for us, as he has done all season.
"It (10 clean sheets in a row) is a brilliant thing for Nick. I think he deserves that accolade. He's been excellent on and offer the pitch in every respect since he signed for the club.
"I can't speak highly enough of him, I can't praise him enough and I can't rate him highly enough. He's a brilliant shot stopper and I think he's in a very good place currently."
After Joelinton was controversially adjudged to have handled before finishing in the 39th minute, the game burst into life following the restart.
The Magpies midfielder somehow blazed over with the goal gaping before Pope quelled mounting Southampton momentum by denying Adams when clean through and expertly clawing away a later effort.
Alexander Isak then teed up Joelinton for the decisive goal before Newcastle academy graduate Armstrong was frustrated by a Stockley Park review having bundled home with the aid of an arm.
Southampton finished a frenetic encounter with 10 men after defender Duje Caleta-Car was dismissed for a second booking four minutes from the end.
"I don't think we were at our best today but I felt we did enough to deserve to win," said Howe.
"There were lots of talking points, obviously VAR involved.
"It's half-time, we're 1-0 up, that's all it is. We're pleased with our work tonight but there's a long way to go."
While Newcastle boosted their quest for a first major domestic trophy since 1955, Southampton were left frustrated and with work to do at St James' Park.
Saints boss Nathan Jones, who also praised Pope, was pleased with his team's display as he expressed further VAR disappointment on the back of having two goals ruled out during Saturday's 1-0 Premier League loss to Aston Villa.
"You can't celebrate a goal any more," said the Welshman.
"You can't show any emotion because you know it's going to VAR one way or another, unless someone picks the ball up from the goalkeeper, runs through 11 players and slots it past the keeper without anything else happening.
"We thought we scored two good goals on the weekend, both overruled by VAR. Tonight is exactly the same.
"I'm frustrated but it's really difficult because these are one-off games.
"The performance level is there, it's just the edges that make or break good teams and seasons - we're just coming out on the wrong end of it."