Last year's Rising Star winner only got better in her second season, polling 15 votes to finish three ahead of Fremantle's tackling machine Kiara Bowers.
The 19-year-old joins dual winner Erin Phillips and North Melbourne's Emma Kearney to have taken out the AFLW's highest individual honour.
"I got to sit next Erin Phillips with my Rising Star medal last year and see her take it so it's crazy my name can be on the same list as those two girls," Prespakis told AAP.
Prespakis' win also makes her the first-ever Indigenous female player to win the medal in the AFL W league.
Prespakis found out from home she was the AFLW's dominant player in the competition's fourth season after a streamed broadcast of the awards due to coronavirus restrictions.
It capped off a spectacular sophomore campaign, with Prespakis also winning the Blues' best-and-fairest for the second time, and on Monday night she was named as an onballer in the All-Australian team.
She averaged 21 possessions during Carlton's six regular-season matches, incredibly collecting the maximum three votes in five of those games.
After her breakout 2019 season, the former No.3 draft pick prepared herself for extra attention on the field this year.
"I was able to put it aside, but take it as a great compliment and just try and enjoy the footy my way," Prespakis said.
"I spoke with my coaches and a few of my teammates about it. They had my back and helped me work through some different ways to get around a tagger and make sure I was OK with it all.
"It's definitely been a year that I won't forget, it's been a great two years, and I can't wait to see what's ahead."
Prespakis has been working casually with a freight company after the AFLW season prematurely ended in March due to the threat of COVID-19.
The Blues defeated Brisbane in their semi-final, but no premier was named because of the unprecedented circumstances of the pandemic's impact on Australian sport.
* AFLW BEST-AND-FAIREST
1. Madison Prespakis (Carlton) 15 votes
2. Kiara Bowers (Fremantle) 12
3. Emma Kearney (North Melbourne) 11
4. Anna Hatchard (Adelaide), Jenna Bruton (North Melbourne) 10
6. Karen Paxman (Melbourne) 9