Background: Iatrogenic injuries due to drug–drug interactions are particularly significant in critical care units because of the severely compromised state of the patient. The risk further increases with the use of multiple drugs, increasing age, and stay of the patient. Objective: The aim was to assess potential drug–drug interactions, evaluate clinically significant potential drug–drug interactions and their predictors in medical intensive care units of tertiary hospitals in Pakistan. Methods: Analysis of patient data collected from medical intensive care units of tertiary hospitals in Pakistan were carried out using Micromedex DrugReax. Various statistical tools were applied to identify the significance of associated predictors. Results: In a total of 830 patients, prevalence of potential drug–drug interactions was found to be 39%. These attributed to 190 drug combinations, of which 15.4% were clinically significant. A significant association of potential drug–drug interactions was present with number of prescribed drugs, age, and gender. In terms of clinically significant potential drug–drug interactions, the association was significant with increasing age. Moreover, one-way analysis of variance revealed a significant difference in the means of potential drug–drug interactions among the four hospitals. Conclusion: A prevalence of 39% potential drug–drug interactions was observed in patients of medical intensive care unit, with 22.8% being clinically significant. These attributed to nine drug pairs and could easily be avoided to reduce the risk of adverse effects from potential drug–drug interactions.