Metastasis is the primary cause of death in squamous cell carcinoma (SCC) patients; thus, identification of highly sensitive tumor biomarkers and therapeutic targets that can be exploited to prevent SCC metastasis and clarification of the underlying molecular mechanism is critically important. Reports have shown that Grainyhead-like 3 (GRHL3) plays a crucial role in tumorigenesis and cancer progression; nevertheless, its functions and molecular mechanism in the development of cancer remain controversial. In the present study, GRHL3 was found to be specifically overexpressed in SCCs, including lung squamous cell carcinoma (LUSC), esophageal squamous cell carcinoma (ESCC), and cervical squamous cell carcinoma (CSCC). In particular, the study revealed that high GRHL3 expression is correlated with poor overall survival (OS) and progression-free survival (PFS) in LUSC patients. Functionally, GRHL3 knockdown suppressed the invasion and migration of SCC cells in vitro and decreased their lung metastasis potential in vivo but had little effect on cell proliferation. Mechanistically, the specific overexpression of GRHL3 in SCCs is orchestrated by a well-known oncogenic transcription factor: tumor protein p63 (TP63). GRHL3 stimulates the expression of heparanase (HPSE), thereby activating the AKT-SRC signaling axis. Taken together, our work reveals a novel molecular pathway through which GRHL3 mediates the metastasis of SCCs, which has important implications for the diagnosis and targeted treatment of SCC.