The 2008 book, created by American writer Joe Kelly and Spanish cartoonist J.M. Ken Niimura, was awarded the gold prize out of 145 entries from 30 countries and areas, the ministry announced on Tuesday.
It portrays a socially isolated girl battling monsters both real and imagined as she comes of age. The three silver prizes went to Asian artists, Pan Liping of China, Cory of Taiwan and Tanis Werasakwong of Thailand. Ten other works were honourably mentioned.
An award ceremony for the Fifth International Manga Award was to be held in Tokyo on Friday.
The award, which excludes Japanese works, was created in 2007 under the lead of manga fan and then foreign minister Taro Aso, who later served as prime minister for a year, to promote manga as a Japanese cultural export.