Antimicrobial (AM) abuse is a major issue in underdeveloped nations, including Ghana, where it poses serious risks to public health. One effective and efficient way to combat AMR is to implement functional antimicrobial stewardship (AMS) programs at health facilities. However, research has shown that, due to several constraints, implementation and compliance in developing countries remain very low. Most studies focus on poor prescription practices and knowledge on AMR, with scant studies on determinants of compliance and its theoretical implications. The purpose of this study is to examine the compliance of healthcare professionals towards stewardship programs and analyze their challenges using the theory of planned behavior. This study employed both quantitative and qualitative methods. This study employed a purposive sampling approach to sample 300 healthcare professionals across 10 hospitals in Ghana. Descriptive statistics and partial least squares structural equation modeling were used for analysis. The results revealed that the majority (71.2) were nurses, while 28.8% were Doctors. Also, most (98%) respondents had training on AMS programs, while only 2% did not. The findings showed that healthcare workers' intention to follow AMS standards was significantly influenced by attitudes (β=0.41, p<0.001), subjective norms (β=0.31, p<0.001), and perceived behavioral control (β=0.38, p<0.001). This study also discovered that behavioral intention and perceived behavioral control both strongly predicted rational prescribing and actual compliance. The qualitative investigation showed that a heavy workload, incorrect diagnosis, inadequate information technology, and inconsistent enforcement of AMS policies all impede compliance. Therefore, it is recommended that hospitals implement interventions that enhance institutional resources and equipment, improve organizational culture, and boost funding of AMS programs. Additionally, this study recommends that the Government, in collaboration with the Ministry of Health, should strengthen AMS programs by providing funds and capacity building at the national and local levels in the country.