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Simple Summary: Cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) possess unlimited self-renewal capacity, resist treatments and induce tumor repopulation after interventions. Here, we observed HNSCC CSCs secreted exosomes containing c-Met, STAT3 (also the phosphorylated form of c-Met and STAT3), CD44, and PD-L1 oncogenic signaling molecules. CSC-derived exosomes, in part, transform fibroblasts (NFs) into cancer-associated fibroblasts (CAFs), establish drug resistance, and an immune-evasive tumor microenvironment (TME). We demonstrated HNC0014, a novel small-molecule drug, suppresses HNSCC tumorigenesis, CSC generation and prevents CAF transformation by decreasing the aforementioned oncogenic signaling molecules' expression in both HNSCC cells and CSC-derived exosomes. Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exosp- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development. [ABSTRACT FROM AUTHOR]