In 1839, Patrick Kenrick's brother, Francis, a former schoolmate of O'Connor in Rome, was by then the Bishop of Philadelphia and invited him to join the faculty of St. Charles Borromeo Seminary, which served his diocese. O'Connor accepted the offer, and arrived in Philadelphia later that year. He immediately assumed the Chair of Theology at St. Charles, of which he became president soon afterwards. In addition to his academic duties, he ministered at the missions in Norristown and West Chester twice a month. He also founded St. Francis Xavier Church in the Fairmount section of Philadelphia. In 1840 he was relieved of his duties as a professor and missionary, but continued to serve as President of St. Charles Seminary.