Hyperlipidemia is a lipid metabolism disorder that requires long-term and daily medication. Leonurine (Leo), an active alkaloid derived from Herba leonuri, can effectively ameliorate lipid profiles in mammals and serve as a candidate antihyperlipidemic agent for clinical applications. In this paper, poly(lactic-co-glycolic acid) (PLGA) microsphere (MP)-based drug delivery platforms were for the first time employed for hyperlipidemia management by encapsulating leonurine nanocrystals (Leo-nano) by a modified solid-in-oil-in-water (S/O/W) double emulsion-solvent emulsion technique. The optimal formulation (Leo-nano@MP) was characterized by a high drug loading and encapsulation efficiency of 19.90 ± 0.82% and 79.62 ± 3.57%, respectively, which followed first-order drug release kinetics over 20 days in vitro. Interestingly, Leo-nano@MP exhibited a unique morphology with a condensed surface yet a porous internal structure, which potentially contributed to the enhanced drug loading and release properties. Furthermore, subcutaneous injection of Leo-nano@MP every two weeks significantly ameliorated the lipid profiles and alleviated liver and kidney injury in HFD-fed rats in comparison with daily administration of free Leo. Besides, no abnormalities in the heart, lung, spleen, and skin tissues at injection sites were observed. In summary, Leo-nano@MP with enhanced therapeutic efficacy, reduced administration frequency, and good biosafety constitutes a promising sustained-release platform for hyperlipidemia management.