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Head and neck squamous cell carcinoma (HNSC) is one of the most prevalent malignancies worldwide. PRKAR1B, a regulatory component of protein kinase A (PKA), has been widely investigated for its potential involvement in tumorigenesis across different diseases. However, its specific role in HNSC remains elusive. In this study, significant differences in PRKAR1B expression were observed across various cancer types. PRKAR1B was highly expressed in HNSC and was strongly associated with poor prognosis in HNSC patients. Moreover, it was identified as an independent prognostic factor significantly associated with clinical parameters. Correlation analysis revealed that PRKAR1B expression was associated with genes such as C7orf50, EIF3B, TBRG4, DDX56, and BRAT1. Additionally, it was associated with TMB and was correlated with the infiltration of immune cells such as M1 macrophages, activated mast cells, and eosinophils. Notably, PRKAR1B was identified as a predictive marker for the efficacy of CTLA-4 inhibitors, with high PRKAR1B expression potentially conferring superior therapeutic responses. Drug sensitivity analysis further suggested that Lapatinib and Erlotinib may be beneficial in HNSC patients with high PRKAR1B expression. Meanwhile, in vitro experiments showed that PRKAR1B knockdown inhibited HNSC cell proliferation and migration. Lastly, PRKAR1B protein expression was upregulated in clinical HNSC samples. Overall, this study thoroughly examined PRKAR1B expression and its prognostic significance in HNSC, investigated related molecular pathways and immune cell interactions, and validated its role via in vitro experiments.