Autophagy is a fundamental process that maintains cellular homeostasis, and secretory autophagy has recently attracted increasing attention due to its emerging role in cancer biology. Our previous work demonstrated that activation of the EGF/EGFR pathway induces secretory autophagy and promotes tumor progression in various cancer types. However, the regulatory mechanisms underlying secretory autophagy in hepatocellular carcinoma (HCC) remain poorly understood. Given that canonical autophagy relies on microtubule-based transport to lysosomes, we hypothesized that secretory autophagy may instead utilize alternative cytoskeletal routes. To investigate this, we performed proteomic analysis of isolated autophagosomes and identified the intermediate filament protein vimentin. Using inhibitors targeting F-actin, β-tubulin, or vimentin, together with total internal reflection fluorescence microscopy, we found that both pharmacological disruption and genetic knockout of vimentin in Huh7-VIM(-/-) cells impaired the translocation of secretory autophagosomes to the plasma membrane. Sequence analysis revealed multiple LC3-interacting region (LIR) motifs within vimentin, and rescue experiments using a triple LIR mutant significantly suppressed secretory autophagosome trafficking. We further demonstrated that EGFR, autophagy-related genes, and vimentin exhibit positive correlations with HCC progression and metastasis, based on analyses of a clinical HCC tissue array and datasets from TCGA and GEO. Additionally, conditioned media (CM) from EGF-treated Huh7-ATG5(-/-) and VIM(-/-) cells exhibited a reduced capacity to promote HCC cell proliferation and migration compared to CM from EGF-treated Huh7-WT cells, likely due to diminished activation of the ERK and STAT signaling pathways. Proteomic profiling of the CM identified HMGB2 and S100A4 as secretory autophagy–dependent cargoes associated with these pro-tumorigenic effects. Furthermore, we found that autophagy deficiency disrupted the formation of HMGB2-containing vesicle-like structures, while vimentin knockout caused cytosolic accumulation of HMGB2 and impaired its secretion. These results underscore vimentin’s essential role in secretory autophagosome trafficking and further support its contribution to HCC progression through vimentin-dependent secretory autophagy.