This explanatory case study aims to formulate a framework of spiritual influence on Science, Technology, Engineering, and Mathematics (STEM)-based research for sustainable development from the perspective of university scientists. This single-site case qualitative study involves seven participants from a Malaysian public research university with a variety of specific research fields. Questions regarding the driving factors of their research strategy for sustainable technology developments were asked. Consequently, the main driving factors on using STEM approaches for sustainable developments are career competency enhancements. This theme can be proven with elements, such as STEM for enhancing the ability to expand a specific field contribution, improving interdisciplinary management, obtaining outsource support, and enhancing innovative capability. Meanwhile, spiritual influence on sustainable development is a part of the philosophy of participants and can be proven through the elements of moral and ethical beliefs with respect to religious values in their scientific career and STEM-based research practice. Therefore, the influence of spirituality is a crucial concept, which can ensure social, emotional, economic, and environmental sustainability development. This framework is built among limited participants. Thus, confirming this framework by using a wide range of samples is encouraged. Moreover, this study generally has implications for sustainable development using STEM-based practice for specific field expertise. The concept aims to provide remarkable contributions to the growth of comprehensive, holistic, and sustainable development and to extend the current literature on STEM research approaches by inculcating spiritual elements.