BACKGROUND: Adherence to chemotherapy treatment requires collaboration and sincere agreement between healthcare providers and patients. Poor medication adherence is problematic as it can lead to reduced effectiveness of the treatment. Poor survival, a rise in relapses, treatment failure, and higher healthcare expenses will result from this. A measure of patient treatment adherence is crucial to attain ideal results, such as curative treatment or improving quality of life. OBJECTIVE: To assess cancer patients' adherence to chemotherapy and related factors patients in the Amhara Region, Ethiopia, in 2022. METHODS AND MATERIALS: Between May 28, 2022, and June 22, 2022, 460 cancer patients in the Amhara region participated in a cross-sectional study carried out by systematic randomized sampling. Data were gathered using an interview-based, previously approved questionnaire. For analysis, the data were first imported into Epi-Data version 4.6 and then exported to the Statistical Package for Social Science version 26. Variables with a p-value of 0.25 were evaluated in a bivariate logistic regression to select a candidate variable for multivariate logistic regression. Variables with a p-value less than 0.05 were deemed significantly associated factors in multivariable logistic regression, and the resulting AOR and 95% CI are displayed for those variables. The Hosmer Lemeshow test was used to confirm the model's appropriateness, and multi-collinearity was verified with a standard error. RESULTS: The proportion of good adherence in the Amhara region is 42.3% (95%CI [37.6-47.6]). A history of comorbidity [AOR = 2.74, 95% CI (1.56, 4.81)], no serious side effects from chemotherapy [AOR = 3.50, 95% CI (1.55, 7.90)], having social support [AOR = 1.52, 95% CI (1.21, 1.95)], being a woman [AOR = 2.17, 95% CI (1.31, 3.60)], and having a family history of cancer [AOR = 3.58, 95% CI (2.22, 5.76)], were associated with good chemotherapy adherence. CONCLUSION AND RECOMMENDATIONS: Compared to other studies, the proportion of poor adherence in the Amhara region was high. Health professionals, families, and government representatives should all work together to provide social support and other systems that will lessen the likelihood that cancer patients with comorbidities may have side effects from chemotherapy.