Background: Chronic kidney disease (CKD) has become one of the most dreadful diseases nowadays. Oman was ranked 51st of the top countries concerning CKD as a leading cause of death, where CKD is responsible for about 2.9% of total deaths. This is a complicated disease that requires a patient to stick to the medication regimen to limit disease progression. Assessing medication adherence among patients with CKD, or its correlates, can slow the progress of this disease. Knowledge about disease and fatigue significantly contributes to CKD patients' medication adherence. Aim: The current study aimed to explore the impact of knowledge and fatigue on medication adherence in CKD. Method: A descriptive cross-sectional study was utilized in this study. Result: Sixty percent of the CKD patients had high medication adherence, and 40% had low adherence. Most participants (94.3 %) did not suffer from severe fatigue, and 99.7% were highly knowledgeable about CKD. The multiple regression showed that age, CKD knowledge and fatigue were significant predictors of medication adherence. Conclusion: Medication adherence remains a challenge in managing CKD progress. Considering the patient’s age, CKD knowledge and fatigue level could help improve adherence and disease self-management. Health care workers are required to provide interventions like reducing the amount and frequency of drugs, providing effective social support, and providing educational counseling, which contributes to improving medication adherence among CKD participants.