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Long-term physical health conditions (LTPHCs) are associated with poorer psychological well-being, quality of life, and longevity. Additionally, individuals with LTPHCs report uncertainty in terms of condition aetiology, course, treatment, and ability to engage in life. An individual’s dispositional ability to tolerate uncertainty—or difficulty to endure the unknown—is termed intolerance of uncertainty (IU), and may play a pivotal role in their adjustment to a LTPHC. Consequently, the current review sought to investigate the relationship between IU and health-related outcomes, including physical symptoms, psychological ramifications, self-management, and treatment adherence in individuals with LTPHCs. A systematic search was conducted for papers published from inception until 27 May 2022 using the databases PsycINFO, PubMed (MEDLINE), CINAHL Plus, PsycARTICLES, and Web of Science. Thirty-one studies (N = 6,201) met the inclusion criteria. Results indicated that higher levels of IU were associated with worse psychological well-being outcomes and poorer quality of life, though impacts on self-management were less clear. With the exception of one study (which looked at IU in children), no differences in IU were observed between patients and healthy controls. Although findings highlight the importance of investigating IU related to LTPHCs, the heterogeneity and limitations of the existing literature preclude definite conclusions. Future longitudinal and experimental research is required to investigate how IU interacts with additional psychological constructs and disease variables to predict individuals’ adjustment to living with a LTPHC.