It was founded by the Sisters of Mercy of the Diocese of Erie, who were led by Borgia Egan, who became the first president of Mercyhurst College.

[5] In 1963, the college prep department separated to form Mercyhurst Preparatory School, which is located behind the university.

On March 27, 1991, Mercyhurst purchased the 100-year-old Redemptorist Seminary in North East and turned it into a branch campus, offering associate degrees and one-year certificates.

[5] In August 2005, the $5 million Michele and Tom Ridge Health and Safety Building was dedicated at Mercyhurst North East.

A $1.3 million residential apartment complex also opened in time for the North East campus' academic year.

[5] Opened in September 2012 is the Center for Academic Engagement, a four-story, 31,000-square-foot (2,900 m2) building that will be set into the rolling hill north of Hammermill Library and feature a skywalk over East Main Drive to connect the two facilities.

[12] The university formerly had a branch campus located 18 miles (29 km) away in North East, Pennsylvania at the site of the former St. Mary's Seminary.

[14] The university has also operated Mercyhurst Corry, a school offering an associate degree in business administration, for over 25 years.

The university's fifth campus, Mercyhurst West, was located in Girard, Pennsylvania, at the site of the former Faith Lutheran Church.

[18][19] Undergraduate students at Mercyhurst all complete the REACH curriculum, which stands for Reason and Faith, Expression and Creativity, Analytical Thought, Contexts and Systems, and Humans in Connection.