Evidence indicated that key changes in macrophage uptake of oxidized low density lipoprotein (ox-LDL) and macrophage polarization in atherosclerotic plaques are closely related to dysfunctional autophagy. Wnt5a (wingless-type MMTV integration site family member 5a) is highly expressed in the macrophage-rich region of atherosclerosis (AS) lesions. However, whether Wnt5a is involved in macrophages autophagy is not clear. In this study, we established macrophages-derived foam cell induced by ox-LDL to explore the effects of Wnt5a/PKCδ pathway on autophagy. RAW 264.7 macrophages were incubated with 60 mg/L ox-LDL for 6h. The expression of autophagy marker, LC3Ⅱ/Ⅰ was significantly increased and p62 was decreased obviously. Moreover, the expressions of Wnt5a, PCKδ and STAT3 were also elevated. Knockdown of Wnt5a reduced the expressions of LC3Ⅱ/Ⅰ and PKCδ, induced the expression of p62, inhibited cellular lipid accumulation. Furthermore, PKCδ inhibitor (Rottlerin) was downregulated the levels of LC3Ⅱ/Ⅰ and STAT3, upregulated p62 level, inhibited cellular lipid accumulation. Therefore, ox-LDL induces autophagy in macrophages may be associated with Wnt5a/PKCδ signaling pathway. The present study indicates that Wnt5a/PKCδ signaling pathway may be underlying target for autophagy and drug intervention.