It has been reported that hyperlipidemia can induce meibomian gland dysfunction (MGD). Lycium barbarum polysaccharides (LBP) has been proven to improve abnormal blood lipids. However, it is still unclear whether LBP exerts a protective effect on MGD caused by hyperlipidemia. This study aims to explore the effect and specific mechanism by which LBP on MGD induced by a high-fat diet (HFD). In present study, we clarified that HFD induced lipid accumulation, inhibited autophagy, and promoted aging by suppressing the AMPK pathway in mice meibomian glands (MG). Not only that, similar results were also obtained in the oleic acid (OA) induced in vitro model (human meibomian gland epithelial cells (HMGECs)). Subsequently, we discovered that LBP administration ameliorated OA-induced autophagy and aging by modulating p-AMPK/AMPK ratio, while also mitigated the lipid deposition in HMGECs. Importantly, using the autophagy inhibitor chloroquine (CQ) largely diminished the protective effects of LBP on OA caused lipid deposition and weakened the autophagy phenomenon, delayed the occurrence of aging and activated the AMPK pathway, which suggested that LBP plays protective effect through enhancing autophagy flux. In summary, these findings demonstrated that LBP alleviated OA-caused lipid accumulation via triggering lipophagy via the AMPK pathway. LBP is expected to be further developed as a new type of functional food additive for treating diet-caused obesity.