Team captain Todd Clever led by example with two tries, while Lou Stanfill and Kevin Swiryn also touched down for the Eagles.
A second penalty from Jeronimo Etcheverry brought Uruguay back into contention at 13-6, shortly after half-time, but the sending-off of prop Mario Sagario dented the South Americans' hopes and Clever's touchdowns saw O'Sullivan's men seal the issue.
Speaking after the game, the former Ireland coach said: "I was very happy with our defence, it went very well today.
"We scrummaged better and stopped their rolling maul, which were the two parts of the game that we needed to improve from last week.
"I feel happy with the way we finished. Uruguay made us work for it and it should be interesting to see how they fare in repechage."
Uruguay will have one last chance to qualify through the cross-continental play-off.
The USA's qualification means Ireland's pool is almost complete, with one last qualifier from Europe to be confirmed next year.
Ireland's opening fixture of the 2011 tournament will be against the USA in New Plymouth on Sunday, September 11, 2011.
The sides met in California last May, when a penalty try and touchdowns from Bob Casey, Ian Whitten and tour captain Rory Best guided Ireland to a 27-10 win over O'Sullivan's charges.
2011 RUGBY WORLD CUP - POOL C:
IRELAND'S POOL C FIXTURES:
Sunday, September 11 - Ireland v USA, Stadium Taranaki, New Plymouth
Saturday, September 17 - Ireland v Australia, Eden Park, Auckland
Sunday, September 25 - Ireland v Europe 2, Rotorua International Stadium, Rotorua
Sunday, October 2 - Ireland v Italy, Carisbrook, Dunedin