Medical errors are prevalent barriers that negatively affect clinicians’ productivity when using a health information system (HIS). In Malaysia, medication errors have critically increased in the past few years and this phenomenon requires immediate academic and managerial attention. This study aimed to determine whether the effective use of HIS could predict the effects of the system, records, service, and knowledge qualities on the performance of clinicians. A total of 1200 surveys were administered to clinicians in different health institutions with HISs. The mediation effects based on 817 usable data were analyzed using partial least squares (PLS). In the path model, results demonstrated that effective use had a positive effect on the outcome variable and partially mediated the positive effects of quality predictors towards enhanced user performance. In other words, effective use of HISs increased the performance of clinicians through the ease of system functions and features, well-organized contents, and minimal data entry errors in EHRs, onsite technical support, and efficiency of drug order entry and decision support tools usage. Future evaluation studies of HIS should integrate effective use, and hospitals must strongly consider this predictor for the system upgrade or new implementation to avert medical errors when the use of the system is compulsory.