Building Information Modeling (BIM) has been widely used in the past decade to enhance the design quality of Heating, Ventilation, and Air Conditioning (HVAC) systems. However, in specialized areas such as pharmaceutical facilities, HVAC design has traditionally relied on Computer-Aided Design (CAD) drawings. This conventional approach does not allow for the simulation of temperature distribution or the verification of system efficiency, which may lead to design failures. To address these challenges in pharmaceutical facilities, this study proposed a BIM-based approach for optimizing HVAC design with Computational Fluid Dynamics (CFD). By employing CFD to simulate the dynamic airflow conditions of pharmaceutical clean rooms, the effectiveness of HVAC systems can be verified. A case study of a clean room HVAC design is presented to demonstrate the workflow. The results of the case study indicated that the pharmaceutical temperature requirements were met within 1 °C during the design optimization simulation, and there was a 95% match in the 72 h temperature mapping test during site validation. The results confirmed that using CFD with BIM not only successfully simulates the design intentions of indoor air quality but also suggests HVAC system optimization for the required clean room design. The findings of this paper contribute to the body of knowledge on overcoming the limitations of the traditional CAD-based HVAC design process and provide valuable insights on optimizing HVAC design with BIM and CFD technologies.