Background and objectives: Drug–drug interactions (DDIs) can create a burden on prescribers to preserve patient safety. This study aimed to identify common DDIs in critically ill patients with chronic kidney disease (CKD) and to evaluate clinical pharmacist's interventions in managing DDIs among these patients. Methods: A prospective observational study was conducted from October 2018 to March 2019. The clinical pharmacist performed a medication chart review; DDIs were identified by using Lexicomp® drug interaction. Based on the occurrence of DDIs, patients were divided into group A: patients with DDI (n = 76) and group B: patients without DDI (n = 15). Clinical pharmacist's interventions were classified according to Pharmaceutical Care Network Europe. The National Coordinating Council for Medication Error Reporting and Prevention was used to categorize the severity outcomes of DDIs and the degree of patient harm. Results: A total of 273 DDIs were identified. The majority of DDIs (63.7%) required close monitoring of the therapeutic outcome to ensure maintaining patient safety. DDIs that needed to be managed by considering therapy modification and avoiding drug combination were accounted for 17.2 and 12.8% of the most common detected interactions, respectively. Seventy-eight percent of DDIs induced no harm to patient. Clinical pharmacist provided different types of recommendations to manage detected interactions, which ranged from therapy outcome monitoring to stop DDIs. A great proportion of pharmacist's interventions (92%) were accepted by prescribers. Compared to patients with stage 3 and 4 CKD, patients with stage 5 had a significantly higher number of DDIs (stage 3 vs 5: p = 0.0019, stage 4 vs 5: p = 0.0456). The number of comorbidities (p = 0.0003) and (p <0.0001) medications were found to be significantly greater in group A. Conclusion: Clinical pharmacist performed important interventions in timely identifying, managing DDIs, and prevention of associated patient harms.