Objectives: This systematic review aims to assess and explore various determinants of cancer- related fatigue. Methods: A systematic search of various determinants of Cancer-related fatigue (CRF) was performed in different databases like PubMed, Google Scholar, Science Direct and Clinical Key dating from 1990 to September 2020. Results: A total of 6115 studies were screened and 95 articles related to determinants of fatigue were retained. Various modifiable and non-modifiable determinants including socio-demographic, clinical, treatment related, plasma biomarker related, genetic, behavioural, concurrent symptoms related and psychological determinants were identified. Depression was one of the significant factors reported in 28% of studies, followed by pain, (17%), performance status (16%), chemotherapy and anxiety (15%). Conclusion: It is recommended that nurses and clinicians should anticipate, identify and take appropriate interventions to manage those modifiable factors. Ultimately, managing the modifiable factors helps in the comprehensive care of cancer patients.