Born and raised outside Buffalo, NY, Santiago-Hudson had an unusual childhood. His father, a railroad worker, and his mother, who struggled with drug addiction, did not live together. While his father was involved with his son, Santiago-Hudson was raised by his mother and her landlady, Rachel Crosby. While his mother dealt with her problems, Crosby, whom the youth called Nanny, oversaw his upbringing with the help of another couple. As one of only 200 blacks in a high school with 1,700 students, Santiago-Hudson encountered racism and his interest in academics dwindled. Nevertheless, he went on to college on scholarships designed for "disadvantaged students" and became interested in acting. Yet, in both college and graduate school he was consistently told that because of his color there were certain roles (mostly classical ones) that he could not play. The closed doors continued when he hit New York City; the Puerto Rican Traveling Theatre rejected him because he could not speak Spanish, while the Negro Ensemble Company rejected him because of the Puerto Rican heritage. By combining his parents names, he eventually won a part in Charles Fuller's "A Soldier's Play" at the Negro Ensemble Company.

It would take nearly a decade before Santiago-Hudson made his Broadway debut in "Jelly's Last Jam". TV roles were slim, although from 1990-1993, he played Captain Billy Cooper on NBC's daytime drama "Another World", a role some might say was "window dressing". He did make several appearances on the NBC primetime sitcom "Dear John" in the early 90s and portrayed a soldier helping to free Cambodian refugee children in "Which Way Home" (TNT, 1991). In 1995, he was alongside fellow Latino Jimmy Smits in Showtime's "Solomon & Sheba". Santiago-Hudson's feature film work began with a small role in "Blown Away" (1994), and, that same year, his was tapped by his Broadway co-star Hines for Hines' directorial debut "Bleeding Hearts".