Background: Supporting organ transplant recipients’ quality of life after surgery continues to be of topical interest to health researchers and applied practitioners. However, literature and guidance on the factors linked to quality of life in transplant recipient athletes remains largely unreported and unconfirmed. Aim: Therefore, in this study we sought to identify significant predictors of quality of life in an international sample of organ transplant recipient athletes (N = 99, Mage = 53.12, SD = 13.70). Method: Adopting a cross-sectional design, we collected the study data during the 2019 World Transplant Games using online and pen-and-paper surveys that consisted of demographic items, health, and physical activity-related measures (i.e., Task and Ego Orientation in Sport Questionnaire, Fatigue Severity Scale, Assessment of Physical Activity Questionnaire, Physical Activity Enjoyment Scale). Predictor variables in the study were broadly summarised into three categories namely demographic factors, sport-related factors, and levels of fatigue with physical and mental quality of life functioning as the outcome variables. Results: Hierarchical regression analyses exposed fatigue to exert a significant negative influence on both mental and physical quality of life perceptions explaining 49% and 64% of the variance in these variables respectively. Conclusion: It is recommended that transplant athletes’ level of fatigue should be routinely measured and closely monitored in sport settings as it has a negative bearing on quality of life that may act as a potential barrier to sport participation and enjoyment.