The Spaniard, runner-up in 2010 and 2011 in the second of the Ardennes Classics, rode away from all his rivals on the infamous final climb of the Mur de Huy.
The Katusha rider justified the hard work done by his team-mates with a devastating burst on the final portion of the 1.3km 'wall' which has an average gradient of 9.3% but with ramps of 19%.
He had time to raise his right arm in celebration as he finished four seconds clear of Michael Albasini (GreenEdge) with defending champion Philippe Gilbert (BMC) taking third in the UCI World Tour race.
"I've had a lot of near misses in a lot of races, but this is the one I wanted to win the most," Rodriguez said.
"In my team I've had to put up with a fair amount of legpulling about my coming so close in Fleche Wallonne before but never winning. I was getting a bit desperate.
"Finally, though, I can put that obsession with getting a win here behind me. It looked straightforward, but you have to have the strength in Fleche and above all on the Mur de Huy calculate exactly how and where you want to make the attack."
On a wet and windy day in Belgium, Dirk Bellemakers (Landbouwkrediet) and Anthony Roux (FDJ) escaped after a frantic opening hour's racing.
They built up a lead of over seven minutes with Sander Armee sandwiched between the pair and the peloton for a long period before being caught with 45km to go.
Their advantage was whittled down, with seven of the 10 climbs on the route coming in the final 53km, and they were caught by the bunch on the eighth of those ascents, the Cote d'Amay, with 15km to go.
Maxim Iglinsky (Astana) attacked on the penultimate ascent, the Cote de Villers-le-Bouillet, but was caught by Ryder Hesjedal who attacked on the descent and was joined by Lars Petter Nordhaug.
Canadian Hesjedal from Garmin-Barracuda and Team Sky's Norwegian powerhouse Nordhaug had a 13-second advantage at the foot of the Huy but were caught on the punishing final climb where Rodriguez burst away.
Belgium's Jelle Vanendert (Lotto-Belisol), who was second in Sunday's Amstel Gold, and Astana's Robert Kiserlovski completed the top five.