Background: drug shortage is a critical with severe negative impacts on patients’ outcome. It is a multifactorial problem in the world leading to increased cost of health, poor treatment outcomes and unnecessary patient referrals. Purpose: this study sought to examine the various causes of drug shortage in Aseer Hospital as a foundational investigation for improvement recommendations. To explore the factors affecting drug shortage and the magnitude of every factor’s influence in drug shortage. Material and methods: this study applied a cross sectional descriptive research design of the quantitative methodology. A questionnaire was electronically sent to the 177 sample for completion. The data was then analyzed using the descriptive statistics of Statistical Package for Social Services (SPSS), version 26. Results: a total of 177 questionnaires were completed. Out of the total sample, male gender dominated by 74.6% (n=132) while 25% were females. The dominant age group was (30-39) years old and most of the sampled pharmacists had bachelors in pharmacy 46.9% (n=83). In terms of experience at work, those who had worked for (5-10) years were the majority. Amongst the variables that contribute to drug shortage, this study found regulation and legislative processes (0.80=77.06%) as the major cause while imbalance between the supply and demand was the least cause (64.3%). There were other factors that contributed to drug shortage such as manufacturing problems (69.80%), drug distribution problems (69.0%) and human factor (65.57%). Conclusion: the study findings are in agreement with most of the previous scholarly findings that cited regulation and legislative process as one of the most causes of drug shortage.