The Omega Pharma-Quick Step rider went clear with 53km to go and rode solo to the Velodrome in Roubaix, finishing 1:39 clear of Sebastien Turgot with Alessandro Ballan claiming third.
The 31-year-old emulated Belgian compatriot De Vlaeminck in the 'Hell of the North' following his victories in 2005, 2008 and 2009.
And it continues an incredible recent run by 'Tommeke' who has been all but unstoppable in 2012 after a quiet 2011.
He is now clear atop the UCI World Tour rankings after also triumphing in prestigious Belgian classics E-3 Harelbeke and Ghent-Wevelgem last month before a record-equalling third career victory in the Tour of Flanders last week.
"When I was all by myself in front, I just went for it as I know there are often disagreements behind over who is going to do the work," said Boonen, who showed four fingers as he crossed the line, his face a mixture of joy and pain.
"It's my greatest (Paris-Roubaix) win. Claiming the fourth in such manner is just great."
The peloton was whittled down, as is customary, as the riders tackled the legendary 257.5km route featuring 27 cobbled sectors and Boonen made his move on sector 12 in Orchies.
He and OPQS team-mate Niki Terpstra then had another burst on the flat before sector 11 with the Dutchman dropped on the 2600m, four-star rated section between Auchy-lez-Orchies and Bersée.
Boonen held a 30 second lead over a chase group of 16 riders, featuring four Team Sky riders, at that point but extended his advantage over the final 10 sections of bone-jarring pavé, which contributed 51.5km of the route.
The chase group could make no inroads and former world cyclo-cross champion Boom went off in solo pursuit of Boonen on sector five with 18km to go.
Ballan, Sky's remaining hope Juan Antonio Flecha and Mathieu Ladagnous caught the Rabobank rider on sector three before the FDJ man punctured.
But they were competing for nothing more than a podium finish by the finish and the trio were caught by Europcar's Turgot and Terpstra in the Velodrome with the Frenchman snatching second from BMC's Ballan, third in 2006 and 2008, by the narrowest of margins.
Flecha, Terpstra and Boom completed the top six.
Farnese Vini-Selle Italia's Tour of Flanders runner-up Filipo Pozzato, who tracked Boonen's initial move, saw his hopes end with a crash on the cobbles with 50km remaining.