The result ensured Serbia won Group Seven with a match to spare and reached their first major tournament as an independent nation. They played in the 2006 finals as Serbia & Montenegro.
Striker Nikola Zigic headed Serbia into a 37th-minute lead before second half goals from Marko Pantelic, Zdravko Kuzmanovic and a late Milan Jovanovic brace completed the rout.
The win took Serbia to 22 points, ahead of France who have 18 points and will finish runners-up following a 5-0 win over the Faroe Islands that clinched a place in the playoffs.
Zigic struck against a subdued Romania from Milos Krasic's corner and the home side ran riot once strike partner Marko Pantelic drilled in the second five minutes after the break.
Substitute Kuzmanovic made it 3-0 with an unstoppable shot that went in off the underside of the bar after being set up by Pantelic, before Milan Jovanovic put the icing on the cake with two superb solo efforts.
The left winger drove in the fourth from 20 metres in the 87th and then weaved past a defender before unleashing a scorcher from the edge of the penalty area in injury time.
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Serbia coach Radomir Antic, who took over from Miroslav Djukic only two weeks before the qualifiers began in 2008, was elated with his team's success.
"We have written a new page in Serbia's soccer history and the authority we have shown throughout the qualifying campaign gives us plenty of reason to believe that we have a very bright future," he told a news conference.
"Days like this make life worth living and we're absolutely delighted. This is a generation of good players and great characters... they deserve the lion's share of the credit for bringing so much joy to the entire nation."
The fans, sporting national flags, team shirts and scarves as they drove through the city in a seemingly endless motorcade, saluted the players who paraded alongside in an open-top bus.
However, Serbia defender Branislav Ivanovic refused to get carried away after their most impressive qualifying performance.
"We've done a fantastic job and I think we have earned our spot in South Africa with consistent and high-quality performances throughout the campaign," he told Reuters.
"But it's too early to say how far we can go in the finals, there is a long way to go until it starts and what we need to do is keep up the good form and steer clear of injuries.
"Tonight's game was an opportunity we simply had to take and the opening two goals really took the pressure off."
