It's 12 years since their only other meeting, the quarterfinal of the 2010 World Cup in South Africa, when Uruguay striker Luis Suarez deliberately stopped Dominic Adiyiah's goal-bound header with his hands in the final minute of extra time. It triggered a sequence of events that ended with Ghana exiting the tournament in the most dramatic fashion and denied Africa its first World Cup semifinalists.
It's a moment that still stings so much that Ghana FA president Kurt Okraku said when the draw was made for Qatar: "It will be revenge time."
For some Ghana fans, even knocking out Uruguay on Friday will not be enough to erase the memory of Johannesburg.
Suarez's actions ended Ghana's involvement at the World Cup but also prevented a moment of history for African football, which has still had only three teams (Cameroon in 1990, Senegal in 2002 and Ghana themselves in 2010) reach a quarterfinal, let alone go any further.
But it wasn't just Suarez's blatant save on the goal-line which angered an entire continent.
Suarez watched the resulting penalty from the mouth of the tunnel after Portuguese referee Olegario Benquerenca had shown a red card.
Asamoah Gyan smacked the ball off the crossbar and cameras caught Suarez celebrating wildly.
The game, which finished 1-1, was eventually decided by a penalty shootout, won 4-2 by Uruguay. Unrepentant afterwards, Suarez branded his intervention "the hand of god" -- a nod to Diego Maradona's handball goal for Argentina against England in 1986.
"Suarez cheated us," former Ghana defender John Paintsil, who played that night, told ESPN.
"I'll always remember what he did, which is not part of the rules of football. We were cheated by him. Using both hands on the line and doing it deliberately to stop us going to the semifinal, I would say Suarez wasn't a professional. He cheated."
Suarez, now 35, is part of the Uruguay squad in Qatar and could line up against the country where he's been considered a villain for more than a decade.
"It's payback," Ghana fan Joseph Dadson told ESPN. "When the draw was made everyone in Ghana thought: 'Finally a chance for revenge.'
"It was the first time Africa had hosted a World Cup and it was the first time an African team was going to go to a semifinal and it didn't happen and it was all because of Suarez. He stole it from us.
"It was devastating, and not just for Ghana but the whole of Africa. At that moment, the whole of Africa was behind Ghana and the defeat and how it happened was too much. It was devastating."
Joseph has made the 6,000-mile (9,650km) journey from Ghana to Doha to support his team during the group stage. He will stay longer if Suarez is vanquished on Friday.
"It's a very big game," he added. "We were the better team in 2010 and it's time to finally prove it."
Whether it's Ghana or not, Paintsil is hopeful 2022 is the year an African team breaks into the last four of a World Cup.
Reigning Africa Cup of Nations champions Senegal have already booked their place in the round of 16 -- they play England on Sunday -- and Ghana are sure to follow if they can beat Uruguay.
As a continent on football's biggest stage, Africa are still playing catch-up with counterparts in Europe and South America because, up until France '98, they were only guaranteed three qualifiers, where now it's five. In 2026, when the World Cup is expanded to 48 nations, Africa will be guaranteed nine participants.
Perhaps more importantly, African players are joining Europe's top clubs with increasing regularity and in October, Senegal's Sadio Mane, once of Liverpool and now playing for Bayern Munich, was voted as the world's second-best player.
Progress is also being made on the touchline and for the first time, each African nation at the World Cup is being managed by an African coach. Ghana are led by 47-year-old Otto Addo, who has coaching experience with Borussia Dortmund, where he was once a player.
"If you look at all the big European teams, there are African players there and we have African coaches here," Joseph said. "African success is just around the corner."
Ghana will hope that beating Uruguay can be the platform for another memorable campaign but when Paintsil sits down to watch the game, there will still be a nagging feeling of what might have been. It was Paintsil's free kick into the penalty area which prompted the chaos at the end of the clash in 2010 and it's not easily forgotten.
"I've got nothing against Suarez, he did what he did for his country," he said. "Mistakes are part of human beings but even after 12 years, I'm still disappointed with what he did.
"It was a huge thing he did for the whole of Africa, not just Ghana. Ghana would have been the first African country to be in a semifinal but the way we were going, we were going straight to the final and winning the trophy because we had so much belief.
"We felt that the whole world was behind us, not just Africa. It was a huge disappointment."
Paintsil insists that despite Ghana's history with Suarez, the Uruguayan would still be welcome in the country if he ever decided to pay a visit.
Joseph, however, is not so sure.
Could he ever forgive Suarez? "We'll see on Friday," Joseph laughed.