Brown, who was forced to end her 2021 season early due to shoulder surgery, had shown signs of improvement with FDJ Nouvelle-Aquitaine Futuroscope and briefly led La Doyenne by as much as 20 seconds ahead of the final ascent.
The Victorian made her move between the last two climbs but was soon met by Olympic champion Annemiek van Vleuten, who soloed her way to an astonishing 89th career win at the age of 39.
Van Vleuten's victory came 43 seconds sooner than Brown, though the 29-year-old held firm in the final sprint to seal second place ahead of Dutch star Demi Vollering and the chasing pack.
It was a victory of sorts for the Australian, who had been yearning for the podium after taking the national time trial title in Ballarat at the start of the year and earning seventh place at the Tour of Flanders.
"I guess I expected to maybe be on the podium earlier this season, so it was a relief to finish my classics with a podium place," Brown said.
"I really love this race, so I am happy with second here."
Marta Cavalli had been tasked with leading the team at the Belgian 'Monument' but shifted her focus to Brown's benefit after fatigue set in on the 142.1-kilometre course.
The Italian was delighted with Brown's performance, one that led all Australian riders as BikeExchange-Jayco's Amanda Spratt finished in 10th place.
"It's a good result for Grace as she did not have an easy first part of the year," Cavalli added.
