Giorgian De Arrascaeta's double earned all three points for Uruguay, but it was ultimately not enough to see them through to the World Cup last 16, thanks to a late Hwang Hee-chan winner for South Korea in the other Group H match which meant the Asian side leapfrogged Uruguay on goals scored.
De Arrascaeta netted two first half goals to see Diego Alonso's side 2-0 up, and that is how it finished, despite the best efforts of La Celeste to seek a late third which would have taken them back above South Korea.
This all came after Andre Ayew missed an early penalty for Ghana, reigniting flashbacks to Asamoah Gyan's penalty miss in this fixture at the 2010 World Cup.
As the game entered extra time, Ghana needed two goals and Uruguay needed one themselves, causing both sides to throw caution to the wind and producing one of the most frantic endings to a game at this World Cup.
There was plenty of needle in this match, both beforehand and during the game, as the 2010 World Cup quarter-final between the sides remains fresh in the minds of Ghanaian supporters after a late Luis Suarez handball denied them a win, before Gyan would go on to miss the resulting penalty.
Sergio Rochet is arguably the most unfortunate man to be packing his bags from this World Cup, as his heroics kept Uruguay well in contention right until the end.
The first notable moment of the game saw him save Andre Ayew's penalty in the first 20 minutes, after Rochet brought down Mohammed Kudus in the box and a lengthy VAR check ruled Ayew onside in the build up.
It was a poor penalty from Ayew and Ghana very rarely threatened for the rest of the game, until it was too little too late.
De Arrascaeta took control of the game himself, getting on the end of a rebound after Lawrence Ati-Zigi spilled Luis Suarez's shot to nod home from on the goal line.
Just moments later, he scored a much more eye-catching strike after some nice build up involving Suarez and Darwin Nunez, as the Flamengo midfielder fired home a lethal volley underneath the body of Ati-Zigi to make it 2-0 on the half hour mark.
De Arrascaeta was quite fortunate to not receive any punishment for a perceived stamp on Alidu Seidu late in the first half though, with VAR deciding not to get involved.
Facundo Pellistri had the best chance for Uruguay to clinch a third, as he fired wide from 12 yards out in what would be his final involvement with 25 minutes to go.
Uruguay felt they had two clear shouts for a penalty in the second half, but referee Daniel Siebert decided against giving one after Daniel Amartey's lunge on Nunez despite going over to the monitor to have a second look, and Edinson Cavani was furious to be denied a spot kick of his own in injury time.
Rochet continued his heroics when he superbly diverted Kudus's venomous volley onto the post with 10 minutes remaining, but Uruguay continued to put most of the pressure on in the second half, knowing that another South Korea goal in the other match in the group would put them out, and those fears came true with Hwang's goal in the 91st minute against Portugal.
That led both sides to go all out for progression, with Ghana needing two goals, they opened up hoping Uruguay would become desperate knowing they needed just one, so neither side prioritised defensive organisation as they entered eight minutes of injury time, but neither side could find a goal.
The 2-0 scoreline here means that the unlikeliest of outcomes ensued, with South Korea advancing to the last 16 at the expense of these two sides, meaning Uruguay exit at this stage for the first time since 2002.