Slurry phase hydrocracking (SPHC) is one of the effective ways to achieve efficient conversion of low‐quality heavy oil. The active‐site structural design of catalysts is crucial to improve the performance but is still challenging. However, up to now, few reviews on the active‐site microenvironments design of catalyst for enhancing SPHC performance have been reported. Herein, this review summarizes the research progress on the active‐site microenvironments regulation strategies of hydrogenation catalysts at the molecular scale for SPHC systematically. Then, based on the problem of low hydrogenation efficiency due to the easy aggregation and low atomic utilization of molecular catalysts, the design strategies for catalysts on the atomic scale are proposed systematically. Subsequently, the design principles of active‐site microenvironment for hydrogenation catalysts to enhance the SPHC are revealed. Finally, the opportunities and challenges of atomically dispersed catalyst for SPHC are prospected. This review provides an important reference for the design and development of high‐performance hydrogenation catalysts for SPHC of heavy oil.