Background: Recent advancements in the field of medical technology have illuminated that the implementation of virtual reality interventions can be highly effective in managing cancer-related fatigue. Moreover, this innovative intervention has demonstrated a substantial improvement in patients' overall well-being and daily functioning. Thus, it represents a promising alternative to traditional pharmacological treatments by effectively addressing symptoms and enhancing quality of life. Therefore, the integration of this approach signifies a significant advancement in patient care. Nevertheless, despite the ongoing efforts to diversify non-pharmacological treatments, pharmacological interventions are still the predominant method for managing cancer-related fatigue. Aim: This systematic review aimed to evaluate the effectiveness of immersive virtual reality in cancer-related fatigue management, and to explore the main side effects of immersive virtual reality. Methods: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Several online databases were used to find eligible studies in peer-reviewed journals relevant to the study keywords. Specifically, the included studies were systematic reviews and clinical trials that used immersive virtual reality-based intervention among adult patients with cancer and suffering from cancer-related fatigue. As well as were published in the English language from 2014 to 2024. As well as, three researchers independently contributed to study selections, data extraction, and study evaluations from different aspects: including quality assessment, risk of bias, and study synthesis. Results: After an extensive and comprehensive search, a total of ten published studies were included in this review study; 6 articles were quantitative clinical trial studies, and the other 4 were systematic review and meta-analysis studies. The quality of 6 included clinical trials was assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for quantitative studies, the overall result showed that 33.3% of studies rated with moderate quality, no study was rated with low quality, and (66.7%) studies rated as high-quality studies. As well, the quality assessment of all review studies showed that all included systematic reviews and meta-analyses with a low risk of bias and high to moderate power of evidence. The result of this extensive and comprehensive review showed that immersive virtual reality has a significant effect in reducing cancer-related fatigue, however, still, there is a significant variation in the employment of immersive Virtual Reality protocols for cancer symptom management worldwide. Conclusion: Immersive virtual reality is an effective non-pharmacological intervention in reducing and controlling cancer-related fatigue among patients with various types of cancer, as well as being an affordable, cost-effective approach. Nevertheless, there remains a notable gap in the existing literature concerning virtual reality protocols, associated side effects, and the underlying mechanisms by which immersive virtual reality alleviates fatigue. Therefore, further research studies are warranted to address these gaps and advance our understanding in these areas.