Introduction: fatigue among cancer is one of the most commonly and frequently reported symptoms by cancer patients. The cause of fatigue is multifactorial in origin, and its impact varies in range from affecting patients’ daily social life, and physical, mental, economic, and social well-being to becoming a threat to their quality of life. Therefore every cancer patient needs to be screened for fatigue and considered one of the vital signs. Objective: To assess the prevalence of fatigue and associated factors among adult cancer patients, receiving cancer treatment at the oncology unit in Amhara region, Ethiopia, 2022. Method: Institutional-based, cross-sectional study was conducted among cancer patients receiving cancer treatment from May 9th – June 8th, 2022. A stratified random sampling technique was used to select study participants. Data were entered into Epi data version 4.6 and then exported to the SPSS statistical package version 23 for further analysis. Both bivariable and multivariable logistic regression analyses were carried out. P-values <0.05 in multivariable logistic regression were considered statistically significant. Results: Of the total of 458 respondents, 449(98.03%) respondents participated in the study. The prevalence of cancer-related fatigue was 77.3% at 95% CI (73.1-81.1). In statically evaluation poor social support (AOR=3.62; 95% CI: 1.53-8.60), anxiety (AOR=3.13; 95% CI: 1.54-6.36), physically inactive (AOR=3.67; 95% CI: 1.74-7.54), underweight (AOR= 2.03; 95% CI: 1.05-3.90), anemia (AOR= 2.01; 95% CI: 1.04-3.90), treatment modality with surgery (AOR=0.21; 95% CI: 0.06-0.78), combination of chemotherapy and surgery (AOR=3.56; 95% CI: 1.68-7.54), duration of treatment less than 3 cycle (AOR=4.43; 95% CI: 1.53-12.80), treatment cycle between 3-5 (AOR=3.55; 95% CI: 1.38-9.09) were significantly associated with CRF. Conclusion and recommendation: Among adult cancer patients receiving cancer treatment, three fourth (77.3 %) of the respondents have fatigue. Poor social support, anemia, unable to perform exercise, anxiety, underweight, combination therapy, and an early cycle of treatment, were associated with fatigue. Therefore, psychosocial assessment and intervention, nutritional support, early intervention of anemia, and promoting exercise are the key elements to minimizing fatigue among cancer patients. Keywords: Cancer, Fatigue, Associated factor, Amhara region, Ethiopia