Simon Gerrans became Australia's first Liege-Bastogne-Liege winner with a sprint finish in the Spring Classic.
The 33-year-old Orica GreenEdge rider outsprinted Alejandro Valverde and Michal Kwiatkowski to clinch the 100th edition of the one-day race.
"It's an incredible victory, a dream come true," said Gerrans, who won the Milan-San Remo one-day race in 2012.
Britain's Chris Froome, the Tour de France champion, withdrew through illness ahead of the race.
Last year's winner Dan Martin of Ireland crashed on the final corner heading into the finishing straight,
Gerrans' best previous result in the race had been a sixth place in 2009, and he added: "I don't know what I feel right now.
"It's a really tough race at the end, so thanks to my team. They got me to the final. I didn't have good legs but I kept going and thanks to the team I could win.
"You never know in a final like this, the last climb is very tough. I did my best to get to the final bend with the leader."
1. Simon Gerrans (Aus/Orica) 6:37:43"
2. Alejandro Valverde (Spa/Movistar) ST
3. Michal Kwiatkowski (Pol/Omega Pharma - Quick-Step)
4. Giampaolo Caruso (Ita/Katusha)
5. Domenico Pozzovivo (Ita/AG2R) +3"
6. Tom-Jelte Slagter (Ned/Garmin)
7. Roman Kreuziger (Cze/Tinkoff - Saxo)
8. Philippe Gilbert (Bel/BMC Racing)
9. Daniel Moreno (Spa/Katusha) +5"
10. Romain Bardet (Fra/AG2R) +6"