The Chicagoan -- who wrote "My Favourite Thing is Monsters" after being paralysed from the waist down after getting West Nile fever from a mosquito bite -- is the first female since "Persepolis" author Marjane Satrapi to take the honour.
Satrapi won in 2005 for her novel "Chicken with Plums".
Ferris, 55, picked up the award in the western French city of Angouleme Saturday still walking with the aid of a cane, 15 years after being struck down by the illness.
She said she was touched by how her coming-of-age tale of a girl obsessed with monster mags investigating the murder of a Holocaust survivor had found such a global audience.
"I live like a monster and I wrote a book about monsters. When I wrote the book I wondered if I would offend people," she said as she received the prize at the Angouleme Comics Festival, one of the biggest in Europe.
"It is marvellous that all these monsters have come out into the light to reclaim their due."
Ferris, a single parent, took six years to draw the 700-page story as she recovered from the virus, having also lost at one point the power in her right arm.
Art Spiegelman, author of the now classic graphic novel "Maus" about the Nazi death camps, said he "started crying like a big dumb baby" while reading the book, Ferris' first published work.
To make ends meet while she wrote the book, Ferris worked as an illustrator and toy designer, making the "Mulan" line of Happy Meal figurines for the fast food chain McDonald's.
On Thursday, the Japanese manga queen Rumiko Takahashi won the festival's top prize for her life's work, only the second woman to have ever done so.
The hugely prolific Takahashi, 61, is one of the most read authors in the world, with her "Urusei Yatsura", "Maison Ikkoku" and "Rin-ne" series selling more than 200 million copies.