DHCC was first established in 1994 as the Gulf War Health Center at Walter Reed Army Medical Center with a mission to care for Gulf War veterans with war-related physical and mental health challenges. That same year the Defense Department instituted the Comprehensive Clinical Evaluation Program (CCEP) to provide systematic clinical evaluations for the diagnosis and treatment of conditions connected to service in the Gulf War. The Gulf War Health Center developed the tertiary treatment component of the CCEP, a three-week specialized care program for veterans with medically unexplained physical symptoms focused on individual and group therapy, patient education, physical and occupational therapy, and alternative medicine.

DHCC was re-established with its current name in 1999 as one of three Defense Department centers of excellence for deployment health. The center was responsible for coordinating the evaluation of veterans seeking care for post-deployment health concerns using the DoD/VA Post-Deployment Health Clinical Practice Guidelines (PDH CPG), which replaced the CCEP in 2001. DHCC added a second track to its specialized care program for veterans with trauma spectrum disorders or significant challenges with post-deployment reintegration. The program consisted of individualized behavioral health and medical care, group therapy and psycho-education, and complementary and alternative treatments.  The center also offered a one-week educational program for significant others of those experiencing deployment-related health challenges, initiated a significant research portfolio related to deployment challenges, and sponsored a week-long deployment-related health care track at the Army’s annual Force Health Protection Conference.

In 2008, the National Defense Authorization Act (NDAA) provided a congressional mandate for the creation of centers of excellence for PTSD and TBI within the Defense Department. In turn, DHCC became a DCoE center. The NDAA charges the center to implement plans and strategies for the prevention, diagnosis, mitigation, treatment and rehabilitation of posttraumatic stress disorder and other mental health conditions. In 2012, administrative and programmatic oversight of DHCC's specialized care program transitioned to the National Intrepid Center of Excellence and in 2014, the PDH CPG was retired.