When Father Thomas Martin, OP visited Columbus on May 15, 1833, a group of five local landowners (Samuel and Margaret Crosby, Nathaniel and Caroline Medbury, and Phoebe Otis) met with him and proposed to gift property at Fifth and Walnut streets to the Catholic Church provided that a church building be constructed and in use within five years’ time.

The pastors at Saint Remigius also served the Catholics in neighboring cities in addition to the parish's own primarily German congregation.

The present structure was completed and consecrated by bishop John Purcell on January 16, 1848,[7] just as Irish immigrants began to arrive in Columbus to escape the Great Famine.

[7] Columbus native and humorist James Thurber resided in the neighborhood around Holy Cross in his childhood, and made reference to its clock and bell in his works.

[7] The Sisters of Notre Dame left in 1961 after the closure of the school making their tenure at Holy Cross the longest in the community's history in the United States.

[11] Beginning in 1993, the growing Spanish-speaking Catholic population in Central Ohio was served at Holy Cross by the non-geographic personal parish of Santa Cruz, established by bishop James Griffin.

[12] In 2001, due to the congregation's continued growth, its worship site moved to Holy Name Church in the Old North Columbus area.

It features a prominent statue of Jesus on the Via Dolorosa with the inscription “Follow Me”, and clock tower with a steeple and belfry.