De Young was born in St. Louis, Missouri, the son of Amelia (née Morange) and Miechel de Young (originally either DeJong or DeJongh), who was a jeweler and dry-goods merchant. The family was Jewish, of Dutch Jewish descent. He moved with his family to San Francisco, California while he was still young. There, he and his brother, Charles de Young, founded the Daily Dramatic Chronicle newspaper, first published on January 16, 1865. The Chronicle was the predecessor of the San Francisco Chronicle, San Francisco's only remaining daily broadsheet newspaper. De Young was also the director of the Associated Press for many years.
In 1884, he was shot by an irate businessman, Adolph B. Spreckels, apparently due to a negative newspaper article, but survived. The M. H. de Young Memorial Museum in San Francisco's Golden Gate Park is named in his honor.
De Young was the great-great-grandfather of actor Max Thieriot.