Background: Self-regulatory mental fatigue (SRF) is commonly experienced after sustained mental and physical effort that requires people to self-regulate behavior, emotion, and movement. Its occurrence suggests that attempts at conscious self-control cause depletion of an exhaustible resource and could lead to decreased quantity and quality of exercises during physical therapy (PT). Patients typically experience fatigue during PT treatment following musculoskeletal or neurological injury, however, SRF has never been applied to PT although there is a strong theoretical link. Objectives: This paper aims to critically appraise the evidence and introduce the concept of SRF to PT rehabilitation of musculoskeletal and neurological conditions. Objectives are to review the current evidence linking SRF to motor control and learning of rehabilitation exercises, links to other allied health areas; to examine the role of emotional suppression on SRF and how it affects performance of PT exercises; and to review the evidence concerning potential techniques for clinicians to offset or promote recovery from SRF. Major findings: Self-regulatory mental fatigue is a robust concept as shown by the volume of research in the area. However, variable methodology and the novelty of the concept to PT reduce the strength of the body of evidence. Research suggests a theoretical link between SRF and reduced quality and quantity of PT exercise. Self-regulatory mental fatigue can be induced during motor learning and by psychosocial costs of musculoskeletal and neurological conditions. Good-quality evidence indicates that techniques such as quotas and implementation intentions could prove useful clinical tools to decrease the effects of SRF during PT treatment. Glucose mouth rinse or ingestion is supported by the literature but is not a clinically sustainable treatment for SRF. Conclusions: There is a theoretical link between SRF and decreased quality and quantity of therapeutic exercise. In order to decrease the effects of SRF this review suggests strategies such as quotas, implementation intentions, rest periods, and glucose supplementation.