Wilkerson served as a pastor in small churches in Scottdale and Philipsburg, Pennsylvania, until he saw a photograph in Life Magazine in 1958 of seven New York City teenagers charged with murder. He later wrote that as he felt the Holy Spirit move him with compassion, he was drawn to go to New York in February 1958. It was then that he began his street ministry.

Wilkerson is well-known for these early years of his ministry to young drug addicts and gang members in New York City in the 1950s and 1960s. He co-authored a book with John and Elizabeth Sherrill about his work with the New York drug addicts, The Cross and the Switchblade, which became a best-seller. Included in the book is the story of the conversion of gang member Nicky Cruz, who later wrote the autobiographical Run Baby Run about his own life. The Cross and the Switchblade has sold over 50 million copies in over thirty languages since it was published in 1963. In 1970, a Hollywood movie based on the book starred Pat Boone as Wilkerson and Erik Estrada as Cruz. The book was included among the 100 most important Christian books of the 20th century.