Effective thermal management is critical for spacecraft systems, where conventional methods face significant challenges due to weight, size, and environmental constraints. This study addresses these issues by integrating microfluidics and nanofluids to enhance the performance of cooling technologies for spacecraft applications. Electrowetting heat pipes (EHPs) are investigated as a novel solution, leveraging electric fields to overcome limitations in traditional wick-based systems, enabling efficient and precise heat transport across extended distances. The research also explores the use of nanofluids, characterized by their superior thermal conductivity, convective properties, and boiling performance, to further improve heat transfer efficiency. Experimental validations by DARPA’s Intra/Inter Chip Enhanced Cooling (ICECool) thermal packaging program demonstrates that microfluidic cooling solutions effectively manage heat dissipation in high-density 3D integrated circuits (ICs), a critical component for future spacecraft electronics. While the findings underscore the potential of these innovations to revolutionize spacecraft thermal systems, challenges such as nanofluid stability, material compatibility, and the scalability of microfluidic designs must be addressed. This paper underscores the potential of these innovations to revolutionize spacecraft thermal systems, paving the way for more reliable and efficient missions. Additionally, the system’s adaptability and potential for large-scale implementation suggest its applicability beyond space missions, including advanced cooling solutions for upcoming AI infrastructure with high computational requirement and therefore high energy dissipation.