Background Increasing healthcare costs, particularly in Low- and Middle-Income Countries (LMICs) like Egypt, highlight the need for rational economic strategies. Clinical pharmacy interventions offer potential benefits by reducing drug therapy problems and associated costs, thereby supporting healthcare system sustainability. Objective This study evaluates the economic impact and clinical benefits of clinical pharmacy interventions in four tertiary hospitals in Egypt by implementing an innovative tool for medication management, focusing on cost avoidance and return on investment (ROI), while accounting for case severity and drug therapy problem (DTP) resolution. Methods Utilizing a digital tool, cost avoidance was assessed by considering the severity of patient cases and the effectiveness of clinical pharmacists’ interventions in resolving identified DTPs. Additionally, ROI was calculated by incorporating both full-time equivalent (FTE) and non-FTE costs to evaluate the overall economic impact of clinical pharmacy services over a six-year period across four tertiary care hospitals in Egypt. Results Over six years, a total of 492,612 patients were reviewed, leading to 19,240 comprehensive clinical pharmacy interventions. These interventions achieved an 88.63% resolution of DTPs, significantly reducing patient risk by preventing adverse DTP consequences, resulting in a total cost avoidance of EGP 265.32 million (USD 8.60 million) and an average ROI of 7.6 (760%). This underscores the substantial economic impact of clinical pharmacy services, particularly in LMICs and countries transitioning to universal health insurance coverage, where cost efficiency and patient safety are critical. Conclusion This study underscores the importance of clinical pharmacy interventions in improving healthcare outcomes and generating significant economic benefits, particularly in low- and middle-income countries. By accounting for case severity and the level of DTP consequences, along with the efficiency of clinical pharmacist-led interventions in resolving DTPs, the economic impact of these services can be more accurately evaluated. These findings are essential for informing policy decisions, highlighting the critical role of clinical pharmacy services in supporting healthcare systems facing economic constraints.