Simon's compatriot Lou Jeanmonnot took silver, 53.1 seconds behind, with Lora Hristova securing a surprise bronze for Bulgaria.
However, it was Simon's composure that stood out as she improved from a 21st place in Beijing to top of the podium in Anterselva.
After a season that started slowly, the 29-year-old peaked for the Milan Cortina Olympics, displaying nerves of steel to anchor the France team to victory in the mixed relay on Sunday.
She was imperious on Wednesday in the individual race, brushing off the single miss and skiing with power and purpose.
"It's incredible, it's incredibly emotional. It's come full circle, one of the best sporting days of my life," she told French TV.
With the top-ranked racers bunched in the middle of the pack and the field starting at 30-second intervals, competitors skied five three-km laps, stopping four times at the range and alternating between shooting from prone and standing positions.
The winner is decided by the lowest overall time, but each miss on the range adds a hefty one-minute penalty, making precision a priority.
With tough conditions in the snow and jangling nerves on the shooting range, plenty of the top contenders cracked under the pressure, but unlike in Beijing, Simon was able to keep calm to secure the win.
"Four years ago, I completely collapsed on that last shoot because I couldn't handle the pressure, because I didn't have what it takes. Today, I got my revenge, and it's incredible," she beamed.
Jeanmonnot did her best to challenge in tough skiing conditions, but her second miss proved to be the difference, and she could not close the gap on the last lap.
While delighted for her teammate, Jeanmonnot wanted more for herself.
"It's a mixed bag because on skis I'm doing very, very well, but conversely, on the shooting range, I'm putting a bit of pressure on myself," she said.
"I'm tense because I really want to go for it, very proud of myself on skis, a little less so on the shooting range."
There was huge joy for Bulgaria as outsider Hristova shot flawlessly to claim their first biathlon medal since Irina Nikulchina's bronze in the 10km pursuit at Salt Lake City 2002.