The present study aimed at investigating the influence of lipid excipients on protein carriers when proteins are encapsulated in lipid and PLGA hybrid particles. PLGA and lipid hybrid microparticles (MP) were prepared by a double emulsion method, and lysozyme was used as the model protein. The encapsulation efficiency (EE) of lysozyme in hybrid MP, particle surface morphology, as well as the release profile of lysozyme were investigated. The results showed that higher content of PLGA in the hybrid MP resulted in better EE of protein and smoother surface of the MP. Burst release of lysozyme from the MP was positively correlated to the chain length of acyl groups in lipids as well as the content of lipids in the hybrid MP. The polymorphic form of lipids in the hybrid MP affected both the EE of protein in the MP and the protein release from the MP, suggesting that EE of protein in the hybrid MP and the protein release profile could be regulated by changing lipid excipients as well as the level of lipids in hybrid MP. The present study provides a good basis for further investigation of the application potentials of lipid and PLGA hybrid MP in drug delivery.