As the fifth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) is a leading global health burden. Despite therapeutic advancements, the survival rate has remained relatively unchanged for the last fifty years. There is an urgent need to better understand the biology of the disease in order to develop more effective therapeutic approaches. HNSCC tumors are dysplastic with up to 80% fibroblasts. We recently reported that tumor-associated fibroblasts (TAFs) make HNSCC more aggressive. Furthermore, we reported that TAFs produce hepatocyte growth factor (HGF), which binds to the c-Met receptor expressed on HNSCC to drive aggressiveness. In this study, we demonstrate that HGF increases glycolysis and lactate production from HNSCC. Further, HNSCC-secreted basic fibroblast growth factor (bFGF) induces autophagy and lactate catabolism in TAFs. Although primarily a degradation pathway, there has been a growing appreciation for a novel role of autophagy in cellular secretion. We hypothesized HNSCC induces secretory autophagy in the TAFs, modulating secreted factors, that drives tumor progression. We assessed the role of autophagy inhibition in alleviating TAF-facilitated HNSCC progression, and uncovered a significant reduction in proliferation, migration, and invasion of the cancer cells. This was achieved using 1) siRNA knockdown of Beclin-1, and 2) therapeutic inhibition of the lysosome through chloroquine treatment. We discovered that normal fibroblasts (NFs) from cancer-free patients, placed in co-culture with HNSCC had a significantly upregulated level of autophagy marker LC3-II. We demonstrate that bFGF induces LC3-II accumulation in TAFs. To understand which TAF factors are secreted through an autophagy dependent mechanism, we assessed conditioned media in TAFs with impaired autophagy. Key cytokines, such as IL-6 and IL-8 secreted from TAFs, were identified as autophagy dependent. Rescue of these cytokines in autophagy-inhibited TAF conditioned media restored HNSCC migration. Although autophagy has been identified as upregulated in a variety of cancer types, no one has previously characterized the role of autophagy in HNSCC and associated stromal cells. Further, both early pre-clinical and clinical studies of autophagy inhibition as a cancer therapy have been limited by the lack of a specifically targeted inhibitor. As such, we demonstrate a significant decrease in HNSCC progression in preclinical models by using a new and highly specific small molecule inhibitor of autophagy, SAR405, which inhibits Vps34, an upstream autophagy pathway kinase. In summary, we uncover a novel role for secretory autophagy in the tumor microenvironment which promotes tumor progression, and can be uniquely targeted for therapy.