Sorafenib, a first-line multi-kinase inhibitor, remains the standard treatment for advanced hepatocellular carcinoma (HCC); however, the development of resistance severely limits its therapeutic efficacy. A key contributor to this resistance is the ATP-binding cassette transporter G2 (ABCG2), an efflux protein that actively exports anticancer drug. Autophagy—a conserved catabolic process that degrades and recycles cellular components. While it promotes cancer cell survival under therapeutic stress, contributing to drug resistance. Recently, secretory autophagy, a non-canonical form of autophagy responsible for the non-lytic secretion of cellular cargos, has been proposed as a potential regulator of membrane protein trafficking. However, its role in multidrug resistance remains largely unexplored. To explore the role of autophagy in sorafenib resistance, we first analyzed patient RNA datasets (GSE109211) and found that autophagy-related genes were significantly upregulated in non-responders. Using a sorafenib-resistant Huh7 cell model (Huh7-SR), we observed increased autophagic activity accompanied by enhanced ABCG2 expression at the plasma membrane. Functional assays demonstrated elevated drug efflux capacity and reduced sensitivity to sorafenib in Huh7-SR cells. Notably, suppressing autophagy through ATG5 knockdown or pharmacological inhibition led to a marked decrease in both ABCG2 surface localization and efflux activity. Imaging by confocal and total internal reflection fluorescence (TIRF) microscopy revealed co-localization between ABCG2 and LC3. Supporting this observation, autophagosome purification and protease protection assays confirmed that ABCG2 is localized to the outer membrane of autophagosomes. Further, in silico analysis identified six LC3-interacting region (LIR) motifs within ABCG2, and co-immunoprecipitation assays validated the direct interaction between ABCG2 and LC3. The enrichment of the secretory autophagy regulator RAB37 in both Huh7-SR cells and isolated autophagosomes further supports its involvement in ABCG2 trafficking. Together, these findings reveal a novel LC3-dependent mechanism by which secretory autophagy promotes ABCG2 trafficking to the plasma membrane, enhancing drug efflux and contributing to sorafenib resistance in HCC.