Ordained in 1928, Markoe was assigned to St. Elizabeth's Church, a Black parish in St. Louis. The work was hard, yielded few results, and some of his fellow priests ostracized him. It took a toll, and after twenty years of sobriety, he returned to the bottle. On one occasion, it took half a dozen police to drag the priest out of a bar, as he had taken on its entire clientele. For seven years after that, he stayed at St. Joseph's Infirmary, Missouri, fighting alcoholism.

In 1943, he re-entered the fight. Assigned to St. Malachy's, another Black parish in St. Louis, Markoe and his brother Bill campaigned to desegregate the Jesuits' St. Louis University. Father Claude Heithaus, a sociology professor, publicly asked why the school admitted people of all faiths, but rejected Catholics on account of their color. They won the fight, but John was soon sent ("exiled," some said) to Creighton University, Omaha, where he spent the rest of his days.

Initially it seemed like his Civil Rights days were finished, but they were really just beginning. Omaha, where segregation was still the rule, had a NAACP chapter as early as 1912, and in 1919 it witnessed a race riot. Malcolm X was born there, but Klan activity forced his family's departure. Whitney Young, director of the National Urban League, worked there in the postwar years.

Markoe's official assignment was teaching math, but he worked mainly with the DePorres Club (named for St. Martin DePorres, a saint of African descent), which he organized to educate the public on race. A decade before these issues attracted national attention, the club led sit-ins at Omaha restaurants, boycotted companies with discrimination practices, and organized public marches. Markoe was there at every step. One member said, he "kept us going."

"Cap" (an army nickname) often said, "Racism is a God-damned thing. And that's two words: God-damned." When a Black veteran encountered opposition occupying his new home, Markoe and Whitney Young sat on the stoop for neighbors to see, while DePorres Club members moved the family in. John Howard Griffin, author of the controversial 1961 book Black Like Me, said Markoe was "in the cauldron when most of us were in diapers."

By the 1960s, the Civil Rights Movement was in full swing, and Markoe was a revered figure among Jesuits. He was slowing down, but even in old age, he had many visitors. One priest noted: "They come from the ghetto most mornings: the poor, the alcoholics, the mentally depressed. Cap offers them what encouragement he can." As race riots swept America in 1967, the dying priest told fellow Jesuits never to "give an inch."

At Markoe's funeral Mass, Father Henri Renard, the homilist (and close friend), called him a fearless character who fought for the "the poor and oppressed." John Markoe is one of the unsung heroes of the Civil Rights movement, which is how he wanted it. Unassuming and modest, during his fifty years working with the African-American community, he never sought attention for himself. Like St. Ignatius Loyola, another ex-soldier turned priest, he embodied the Jesuit ideal of "men for others."