Wissa rounded off a historic night for the Africans with a fine strike in stoppage time for his third goal of the tournament.
Uzbekistan knew before kickoff they were realistically eliminated, given the massive swing in goal difference they would need to progress.
However, Italian great Fabio Cannavaro stressed the importance of a win as a legacy for their first World Cup appearance and his players flew out of the traps.
Shomurodov smashed home after just 30 seconds but was flagged offside.
Uzbekistan’s captain and all-time leading scorer had to wait just 10 minutes longer for his moment to savour.
The Istanbul Basaksehir striker produced a sumptuous lob over Mpasi from a narrow angle.
Nathanael Mbuku thought he had brought the Congolese level with an equally fine strike that arrowed into the top corner.
However, after a VAR review, Mbuku was punished for a soft foul on Sherzod Nasrullaev in the build-up as his hand brushed the face of the Uzbek defender.
DR Congo coach Sebastien Desabre said Wissa was showing the best version of himself after a poor first season at Newcastle since a £55 million ($73m) move from Brentford.
Wissa scored his side’s equaliser in an impressive 1-1 draw against Portugal but fired wastefully wide with a huge chance to level early in the second half.
At the other end, Shomurodov nearly produced a second sublime lob as this time his effort dropped onto the roof of the net from the edge of the box.
DR Congo were beginning to run out of ideas until a rash challenge from Manchester City’s Abdukodir Khusanov on Wissa gifted them a route back into the game and into the knockout stages.
Wissa picked himself up to calmly send Abduvohid Nematov the wrong way and whip up an explosion of noise from the nearly 70,000 in attendance.
Just two minutes later, the majority of the fans saw the moment of history they came for.
Meschack Elia’s deflected shot held up just enough for Mayele to nip in ahead of Nematov and flick the ball into the net.
Wissa completed the comeback by curling into the far corner from the edge of the area.
Congo’s progress continued a stunning World Cup so far for African sides.
Only Tunisia of the 10 African teams at the tournament have been eliminated, while Algeria can join the eight nations to have progressed to the last 32 in the final group matches later today.
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