Chemokines play a significant role in cancer. CXC-motif chemokine ligands (CXCLs) are associated with the tumorigenesis and progression of head and neck squamous cell carcinoma (HNSC); however, their specific functions in the tumor microenvironment remain unclear. Here, we analyzed the molecular networks and transcriptional data of HNSC patients from the Oncomine, GEPIA, String, cBioPortal, Metascape, TISCH, and TIMER databases. To verify immune functions of CXCLs, their expression was analyzed in different immune cell types. To our knowledge, this is the first report on the correlation between CXCL9–12 and 14 expression and advanced tumor stage. CXCL2, 3, 8, 10, 13, and 16 were remarkably related to tumor immunity. Kaplan–Meier and TIMER survival analyses revealed that high expression of CXCL1, 2, 4, and 6–8 is correlated with low survival in HNSC patients, whereas high expression of CXCL9, 10, 13, 14, and 17 predicts high survival. Only CXCL13 and 14 were associated with overall survival in human papilloma virus (HPV)-negative patients. Single-cell datasets confirmed that CXCLs are associated with HNSC-related immune cells. Thus, CXCL1–6, 8–10, 12–14, and 17 could be prognostic targets for HNSC, and CXCL13 and 14 could be novel biomarkers of HPV-negative HNSC.