Background: Cancer is the leading cause of death worldwide, and poor adherence to chemotherapy has become a public health issue in developing countries, including Ethiopia.Objective: To assess chemotherapy adherence and associated factors among patients with cancer in the Amhara Region, Northeast Ethiopia.Methods: A hospital-based prospective cross-sectional study design was employed, and a total of 460 cancer patients were enrolled using a systematic random sampling method at Felege Hiwot and Dessie comprehensive specialized hospitals from May 15, 2022, to July 15, 2022, in the Amhara region. The data was gathered through a review of medical records and a face-to-face interview and entered into Epi-Data version 4.6 before being exported to SPSS version 26 for analysis. Furthermore, at 95% confident interval (CI), multivariable binary logistic regression was used, and variables with P-values of <.05 were found to be significant.Result: The overall response rate in this study was 94.1% (433), with 42.3% of patients adhering to chemotherapy. Moreover, having a family history of cancer [AOR = 3.58, 95% CI (2.22, 5.76)], being female [Adjusted Odds ratio (AOR) = 2.17, 95% CI: (1.31, 3.60)], having no history of comorbidity [AOR = 2.74, 95% CI (1.56, 4.81)], having side effects from chemotherapy [AOR = 3.50, 95% CI (1.55, 7.90)], and having social support [AOR = 1.52, 95% CI (1.21, 1.95)] were important predictors of chemotherapy adherence.Conclusion and recommendations: Patients' understanding of illness characteristics and treatment should be improved through health education. Involving family members in the treatment plan will also improve adherence to chemotherapy in this context.