A "rez" man himself, Tomson Highway has transformed the spiritual and cultural lessons of his youth into drama. He was born in Manitoba, Canada, on his father's trap-line ("in a tent, like all his brothers and sisters") on December 6, 1951 (some sources cite 1952). He spoke only Cree until the age of six, when he was sent to study at a Roman Catholic boarding school. He stayed there until he was 15, visiting his family only two months each summer. After finishing grade nine, Highway was sent to high school in Winnipeg, where he lived with various white foster parents. He graduated in 1970.

Since he was a "musical prodigy" in high school, Highway next spent two years at the University of Manitoba studying piano—a pursuit that he continued the following year, studying to be a concert pianist in London. After this year abroad, Highway returned to Canada, where he continued his studies at the University of Manitoba and the University of Western Ontario (from where he graduated with a Bachelors of Music Honors in 1975). However, he stayed an extra year to complete the English courses required for a Bachelors of Arts degree; during this time, he met and worked with James Reaney, one of Canada's more respected playwrights and poets.

With his studies completed, Highway followed his humanitarian impulses and began seven years' work with The Native Peoples' Resource Center in London, Ontario, and The Ontario Federation of Indian Friendship Centers in Toronto. It was during this time that he traveled extensively through the reservations of Canada, meeting and observing scores of Native people in streets, bars, prisons, and friendship centers. Upon turning thirty, Highway began his career as a playwright, presenting his work to Native audiences on reservations and in urban community centers. With the 1986 premiere of The Rez Sisters, Highway's artistic career began to blossom.

Speaking of his inspiration in creating The Rez Sisters's female protagonists, Highway remarked to the Toronto Globe and Mail's Ray Conlogue, "I am sensitive to women because of the matrilineal principle of our [Cree] culture, which has gone on for thousands of years. Women have such an ability to express themselves emotionally. And as a writer, you've got to express emotion." This "expression of emotion" found in The Rez Sisters proved impressive: the play received numerous honors and played to sold-out audiences across Canada. After its success, Highway wrote a collection of monologues, Aria and his "flip-side'' to The Rez Sisters, Dry Lips Oughta Move to Kapuskasing (1989), which features seven Indian men. Like its counterpart, Dry Lips won numerous awards, including four Dora Mavor Moore Awards. Highway served as the artistic director of Native Earth Performing Arts, Inc., Toronto's only professional Native theater company, until 1992. He also co-wrote The Sage, the Dancer, and the Fool, with Rene Highway and Bill Merasty in 1989.