<p>Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Previous studies have suggested that C-Type Lectin Domain Containing 7A (CLEC7A) could affect human cancer progression by regulating M2 macrophage polarization. However, the role of the molecular mechanism of CLEC7A involved in OSCC progression is poorly defined. GEPIA database was used to analyze CLEC7A and specificity protein 1 (SP1) expression, and the relationship between CLEC7A and M2-type macrophage markers (CD163 and MRC1). CLEC7A and SP1 levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). CLEC7A, SP1, RHOA, RAC1, E-cadherin, and Vimentin protein levels were detected using western blot. Cell proliferation, apoptosis, migration, and invasion were detected by Colony formation, flow cytometry, and Transwell assays. The proportion of CD11b⁺CD86⁺ positive cells was detected using flow cytometry. Binding between SP1 and CLEC7A promoter was predicted by JASPAR, and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The biological role of SP1 on OSCC tumor growth was examined by the xenograft tumor model in vivo<i>. </i>CLEC7A and SP1 expression levels were increased in OSCC tissues and cell lines. Furthermore, CLEC7A deficiency could repress OSCC cell proliferation, migration, invasion, M2-type macrophage polarization, and induce cell apoptosis in vitro, as well as hinder tumor growth in vivo. At the molecular level, SP1 was a transcription factor of CLEC7A and promoted CLEC7A transcription via binding to its promoter regions. SP1-activated CLEC7A could facilitate OSCC cell malignant behaviors and M2 macrophage polarization, providing a possible therapeutic target for OSCC treatment.</p>