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Oral squamous cell carcinoma (OSCC) frequently metastasizes, leading to poor patient outcomes. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has been implicated in cancer progression; however, the downstream mechanism driving OSCC motility remains incompletely defined. Cyr61 expression was elevated in OSCC and associated with advanced clinicopathological features. In OSCC cell lines, recombinant Cyr61 enhanced wound closure and Transwell migration and increased intercellular adhesion molecule-1 (ICAM-1) expression at both the mRNA and protein levels. ICAM-1 silencing significantly attenuated Cyr61-induced cell motility, indicating that ICAM-1 is an important downstream effector. Mechanistically, Cyr61 signaling was initiated through integrin αvβ3 and αvβ5, as neutralizing antibodies and siRNAs targeting these integrins suppressed Cyr61-induced migration and ICAM-1 expression. Cyr61 also induced phosphorylation of PLC, PKC, and c-Src, and pharmacological or siRNA-mediated inhibition of these kinases attenuated ICAM-1 upregulation and cell migration. Moreover, Cyr61 enhanced AP-1 activity via c-Jun phosphorylation, increased c-Jun occupancy at the ICAM-1 promoter, and inhibition of AP-1 signaling diminished Cyr61-driven ICAM-1 expression and motility. Together, these data define an integrin αvβ3/αvβ5-PLC-PKC-c-Src-AP-1 axis that transcriptionally upregulates ICAM-1, promoting OSCC migration and providing a mechanistic basis for targeting Cyr61-driven migratory programs in OSCC.