In 1852, the new Archbishop of Baltimore, Francis Kenrick, asked the local Jesuit Provincial to open a new college in response to petitions from the newly elected, anti-Catholic Know Nothing party to ban Catholic teachings from public schools in Maryland.

The following year, the newly renovated church was decorated for the public celebration of the twenty-fifth anniversary of Pius IX's election to the papacy; gaslight illuminations were installed for the occasion but could not be used because of adverse weather.

[5] After World War II the church had seen a sharp drop in the number of parishioners as many city residents moved to the suburbs.

In 1991, the church underwent a $1.7 million renovation to separate the sanctuary from the entrance to give parishioners a place to gather before and after mass.

St. Ignatius Church was built by Louis L. Long, a prominent Baltimore architect, from 1853 to 1856 with the assistance of Henry Hamilton Pittar.

Saint Ignatius church has a free standing altar built by a South Baltimore company featuring hand-carved wood Ionic columns mirroring the external architecture.

Behind the main altar, the church features a painting of St. Ignatius' mystical experience outside Rome at La Storta by Constantino Brumidi.

The paintings are of St. Aloysius Gonzaga, the Patron Saint of Youth, who died of the plague in 1591, and Our Lady of the Way, Madonna della Strata.

The church also sponsors a community outreach program called "Elizabeth’s Closet" that collects and distributes maternity clothing to expecting mothers.