However, thanks to second-round wins over South Korea and the USA respectively, the two nations were pitted against each other in the quarter-finals, which in turn meant that one of them would have the chance to reach the final.
The African outfit had lit up the tournament at times, with Asamoah Gyan, who would later join Sunderland, their leading light.
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It was another man with Premier League experience - Sulley Muntari - who actually put Ghana in front though in the second minute of stoppage time from long range.
There were English connections all over the pitch and another - former Manchester United striker Diego Forlan - drew the South Americans level with a free kick 10 minutes after the restart.
Both teams then had their chances to win the match, but neither could convert and so extra time was required. It was clear that the players were tired during those added 30 minutes, but with seconds remaining, one of the most memorable moments in recent World Cup history took place.
It appeared that Dominic Adiyiah was about to win the match for the Black Stars, but his headed effort was deliberately handled on the line by the then Ajax striker Luis Suarez. He was instantly dismissed and so Gyan, who had played so well up until this point, had the chance to be a real hero from the spot. His effort smashed against the crossbar though, forcing the match into a penalty shootout.
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Suarez, watching on from the sidelines before he returned to the dressing room, was captured on camera wildly celebrating Gyan's misfortune. It drew criticism from a number of people, but it is probably water off a duck's back now following his time with Liverpool.
Gyan made amends of sorts when he scored Ghana's opener from 10 yards, but it wasn't enough to stop his side slumping to a 4-2 defeat.
Uruguay went on to face the Netherlands, but their run was ended by a 3-2 loss.