After graduating Williams started up his own practice making him the first physician to work under the cites railway system. Since this was a time of discrimination Africans were prohibited from hospitals and refused staff positions. In May 1891, Williams opened a Provident hospital and training School for Nurses which made it the first racially integrated hospital with a nursing and intern program. The facility, where Williams worked as a surgeon, was publicly championed by famed abolitionist and writer Fredrick Douglass.
In 1893 Williams pursued to make history again by operating on James Cornish who was brought to Provident for a severe stab wound to the chest. Williams was able to suture Cornish's pericardium, becoming the first person to perform open heart surgery. Physicians Francisco Romero and Henry Dalton had previously performed pericardial operations but were unsuccessful while Cornish was able to live for many years after.
In 1984 Williams moved to D.C. and was appointed Chief Surgeon at Freedmen’s Hospital which helped formerly enslaved African Americans. When the facility had fallen into neglect and had a high mortality rate Williams co-funded a the National Medical Association for black medical practitioners but In 1898 Williams married Alice Johnson and they moved back to Chicago where Williams began working for Province again. He later made trips to Nashville, Tennessee where he volunteered as a clinical professor for Meharry Medical College. He later in 1913 became a charter member of the American College of Surgeons.
Williams experienced a stroke in 1926 and died 5 years later in Idlewild, Michigan on August 4,1991