At first, his ministry was to Catholics in western Pennsylvania.  There were only 21 priests for 45,000 Catholics.  Eventually, through the direction of St. John Neumann, who was his first pastor in Pittsburgh, he and other German speaking priests ministered to German-speaking immigrants.  He went from associate pastor to pastor to the rector of the seminary to the head of the Redemptorists, back to his first love, Missionary work.  During the Civil War, years 1862-1865, he and a few other priests went up and down the middle part of our country giving missions and retreats, dodging bullets and the rough behavior of the soldiers on both sides of the conflict.  He appealed to President Lincoln to release the priests and seminarians from the draft.  He and another priest met with the President, who was very cordial, but could not guarantee that this could be done.  However, none of the students were drafted. 
For three years prior to his transfer to his last parish in New Orleans, Louisiana, he was in charge of the Redemptorist Mission Band.  Blessed Francis Xavier Seelos and a group of other priests would travel all over the middle states, including Missouri, Illinois, Wisconsin, Michigan, Ohio;, Pennsylvania, New York, New Jersey, Connecticut, and Rhode Island.  He not only considered mission work to be important, he wrote to his sister in 1863, “It is properly the work in the vineyard of the Lord; it is entirely apostolic work.”
One of his greatest strengths was in the Confessional.  Blessed Francis Xavier Seelos reminds us of Padre Pio and St. Jean Vianney.  He would spend hours in the Confessional.  He was gentle but firm.  He begged the sinners from the pulpit to come to the confessional.  He said “O you sinners who have not courage to confess your sins because they are so numerous or so grievous or so shameful.  O, come without fear or trembling!  I promise to receive you with all mildness; if I do not keep my word, I here publicly give you permission to cast it up to me in the confessional and to charge me with a falsehood.”  He chided his fellow priests who did not have compassion for penitents; “The priest who is rough with the people does injury to himself….he sins, at least in ignorance…he scandalizes all who see and hear him…Thousands reject the Church and the Sacraments because they have been badly treated by a priest.”