The Spaniard upstaged team-mate and defending champion Joaquim Rodridguez to record the biggest win of his career at the summit of the Mur de Huy.
He finished comfortably ahead of Team Sky's Sergio Henao with another Colombian, Carlos Betancur, taking third in the Ardennes Classic.
A group of around 40 riders hit the foot of the Mur de Huy together as they commenced their third ascent of the 1.3km 'wall'.
AG2R La Mondiale's Betancur went early on the climb, which has an average gradient of 9.3% but has a number of sections at 17% and one corner at 26%.
But in the closing metres he was overtaken by the 31-year-old from Madrid, who claimed the 77th edition of the event and valuable World Tour points.
“Purito (Rodridguez) wasn’t in top shape due to the crash in Amstel Gold and I knew I was in a great shape instead. Joaquim predicted I would win today," said Moreno.
"I’m glad to help Rodriguez, I can’t stand the pressure like he does. I will have my chance as a leader in Tour de Romandie but then in Tour de France and Vuelta a Espana, I’ll be happy to help him in general classification: I’ll just take advantage of the chances I’ll have, just like today."
Pirmin Lang (IAM Cycling) and Gilles Devillers (Crelan - Euphony) attacked after 20km of the 205 kilometre race. They were joined by Jurgen Van Goolen (Accent Jobs - Wanty) and built up a maximum lead of 9:20 over the flat opening quarter of the race.
But that lead was whittled down as they tackled the 12 climbs on the route and they were caught on the Côte de Bohisseau with 47km remaining.
A counter-attack from Romain Bardet and Laurens Ten Dam followed as the riders looped back to Huy for a second climb up the Mur with 31.5km remaining, with Simon Geschke going over the climb in the lead.
Geschke and Ten Dam persisted with their attack on the finishing loop but a large peloton, headed by Phillipe Gilbert's BMC team, kept them within touching distance and they were caught inside the final 10km on the penultimate climb of the Cote de Villers-le-Bouillet.
It all came down to who was the strongest man on the Mur de Huy and many of the race favourites floundered with Ireland's Dan Martin (Garmin Sharp) and Michal Kwiatkowski (Omega Pharma - Quick-Step) completing the top five ahead of Rodriguez and 2006 champion Alejandro Valverde (Movistar).
World road champion Gilbert won the race in 2011 and was third last year but after being prominent in pursuit of Betancur faded to finish 15th, three places behind Peter Sagan who was unable to complete his spectacular spring - which includes wins in Gent-Wevelgem and Brabantse Pijl plus second place finishes in Flanders and Milan-San Remo - with another victory.
Earlier, Marianne Vos won the women’s race for the fifth time. The Dutch rider beat Longo Borghini and South Africa's Ashleigh Moolman.