Mater Dei High School opened in 1949 on the west side of Evansville, Indiana as a Catholic, diocesan, coeducational high school to serve the needs of a growing community. Bishop Henry J, Grimmelsman named the school in honor of Mary, Mother of God, who serves as the school's patroness. The school is one of two Catholic high schools in Evansville and serves the students of Vanderburgh, Posey, Gibson, and Warrick counties.

In 1998, the school contracted with ARC construction for a major addition project which included five science rooms, two computer labs, a chapel, an auditorium, and new administrative offices, new windows throughout the building, and air conditioning. The generosity of the people of the diocese of Evansville made this multimillion dollar undertaking possible.

Recognizing the need to serve diverse learners, in 2000, the school established a resource program that includes a licensed special education teacher and serves approximately 10% of the student body.

In 2011, the Full of Grace: Excellence for Tomorrow Capital Campaign began and has funded many projects, including a media center renovation and expansion, new resource room, tennis courts, artificial turf football field, dedicated baseball field, improvements to the school's entrance on Harmony Way, and auxiliary gym renovation and expansion.