The main objective of this study aimed to assess drug–drug interactions (DDIs) in the cardiac care unit (CCU) and cardiac surgery units and the role of a clinical pharmacist in detecting and preventing the expected DDIs. Methods: This cross-sectional study was conducted in the CCU Units of Nemazee and Shahid Faghihi Hospitals, two referral hospitals in Shiraz, South of Iran, from August to February 2016. Patients older than 18 years, who were admitted and had received >24 h of inpatient services in these wards with two or more medication orders, were included in this study. All medication orders were evaluated by a pharmacist and DDIs were examined based on the Lexi-Interact™ software. In cases with serious DDIs (D or X), the physicians and nurses were informed, and intervention was conducted by a clinical pharmacist. Findings: A total of 3706 medical orders were evaluated. 6478 DDIs were detected, of which, 446 (6.88%) belonged to Classes D and X, and a total of 43.43% of all hospitalizations had at least one DDI. Factors with the most considerable influence on DDIs included an increased number of prescribed medications and patients underlying disease. The physicians accepted 62% of the interventions. The most frequent drugs responsible for interactions of Classes C, D, and X were aspirin, warfarin, and clopidogrel, respectively. Conclusion: This study shows that a significant number of clinical DDIs exist in hospitalized patients, especially among consumers of warfarin and aspirin. The role of a clinical pharmacist in preventing such interactions and safer pharmacotherapy management for hospitalized patients is essential.