N6-methyladenosine (m6A) is the most common internal reversible modification of mRNA, which occurs on the N6 nitrogen of adenosine. Fat mass and obesity-associated (FTO) is a demethylase that erases m6A modification and has recently been linked to cancer. Herein, we explored the role of FTO in oral squamous cell carcinoma (OSCC). High FTO mRNA and protein levels were observed in OSCC cell lines and tissues as compared to normal controls. OSCC patients with high FTO displayed larger tumor size, higher TNM stage, poorer differentiation, and shorter survival time than those with low FTO. Stable knockdown of FTO inhibited OSCC cell viability, colony formation, and tumor growth. Further, FTO depletion increased YAP1 m6A modification at mRNA 3'-untranslated region, accelerating the degradation of YAP1 mRNA, a well-documented oncogene promoting OSCC progression. Importantly, nucleocytoplasmic shuttling of FTO is critical for YAP1 mRNA demethylation and decay following YTHDF2 reading and recognition. Our results highlight the role of FTO in regulating YAP1 mRNA stability, and targeting of FTO/YAP1 axis may be a promising intervention for OSCC patients.