UT Tyler HSC was chartered in 1977 by the University of Texas System Board of Regents.

Located in Tyler, TX, UT Tyler HSC was originally named "East Texas Tuberculosis Sanitarium", established in 1947 as a tuberculosis treatment facility at the location of the retired World War II U.S. Army Infantry Training Base called Camp Fannin.

While research has long been a part of its history, residency programs started in 1985 with Family Practice.

With the addition of the clinical affiliate, UT Health East Texas, plans are underway to extend residency programs in general surgery, trauma surgery, and expand the internal medicine program.

The System also announced it had accepted an $80 million donation from the legacy charity of UT Health East Texas, the East Texas Medical Center Foundation to aid with planning and starting costs, with a hope to beging instruction in fall of 2023.