Epigenetic alteration is one of the common features in cancer progression.1 N6-methyladenosine (m6A) RNA modification regulates RNA metabolism and has been implicated in the development and progression of cancers.2 In our study, we discovered that the expression of methyltransferase-like 3 (METTL3) was significantly elevated in human esophageal squamous cell carcinoma (ESCC) tissues. Ablation of METTL3 inhibited proliferation and migration and induced apoptosis in ESCC cells both in vitro and in vivo. Paclitaxel (PTX) treatment resulted in a significant up-regulation of METTL3 expression within ESCC cells. Mechanistically, METTL3 promoted ESCC development and reduced chemosensitivity to PTX through regulating the mRNA stability of apoptosis-related genes caspase 9 (CASP9) and apoptosis protein repeat-containing 3 (BIRC3). These findings reveal the molecular mechanism of METTL3 in ESCC development and progression, providing new insights for developing molecular diagnosis and therapies for this malignancy.