Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor in the head and neck with a high suicide rate. Numerous studies have indicated that lncRNAs play a significant role in tumor occurrence and development, and that they may serve as promising diagnostic markers and therapeutic targets. The lncRNA HOXB-AS4 is substantially expressed in HNSCC; this work aimed to clarify the role of HOXB-AS4 in HNSCC and to further investigate its potential mode of action. In this study, bioinformatics analysis was utilized to identify differentially expressed lncRNAs from RNA-seq data in the TCGA-HNSCC data set. The effect of lncRNA on HNSCC cell function was assessed using cell function tests. The probable downstream target mRNA of lncRNA was discovered after analyzing the differential mRNA and reviewing the literature. Mass spectrometry was utilized to investigate the signaling pathways it may control. RT-qPCR and western blotting were employed to confirm its regulatory action. HOXB-AS4 was abnormally overexpressed in HNSCC, which was related with poor clinical characteristics and prognosis, as well as promoting HNSCC cell migration, invasion, proliferation, and clone formation. The elevated expression of HOXB-AS4 in HNSCC may play a role in tumor promotion by influencing the HOXB7 gene located on the same chromosome, thereby activating the phosphorylation of AKT. HOXB-AS4 may promote malignancy in HNSCC by controlling the HOXB7/AKT pathway.