Evelyn Stevens (USA) caused quite an upset when she out-sprinted Marianne Vos (Ned) to the line to win in 3 hours 26 minutes and 32 seconds.
Vos, who is the top ranked women's rider in the world, was second, four seconds adrift.
Because Vos was victorious in four of the last five Fleche Wallonne races, it was generally expected that she would win.
Linda Villumsen (NZl) was third (20 seconds adrift) and Lucinda Brand (Ned) was fourth (27 seconds adrift).
It could not be established with certainty whether, and when, a South African female cyclist had ever before achieved a top-10 finish at a World Cup event.
There is a possibility that Anke Erlank, a former local cycling legend might have done it, but it is certainly not a regular occurrence in South African cycling.
Earlier this season, Moolman-Pasio finished 10th in the Trofeo Binda World Cup in Italy.
These two top-10 finishes put her in the 13th position overall in the World Cup standings.
After her fifth place finish, she is also one of the top-40 riders on the UCI rankings.
"Ecstatic and slightly disappointed" is how Moolman-Pasio described her performance in the Fleche Wallonne Femme.
"It was my goal to finish in the top five, so I guess it was mission accomplished."
She said she was caught slightly off-guard by one of Vos's attacks during the last few kilometres, which meant that she had to race hard to catch up again.
With her never-say-die attitude, Moolman-Pasio managed to pass quite a few riders on the legendary Muur de Huy climb.
Stevens and Vos battled it out up the final, impossibly steep slopes of the climb that had been Vos's territory so many times before, but the American managed to out-sprint her rival during the final 30 metres.
Stevens and Vos were the best of a five-rider break that had formed during the final 15km of the 123km race.
They had bridged across the original group of Lucinda Brand, Linda Villumsen and Clara Hughes and this led to a straight battle up the final climb to the finish.