The most prevalent RNA modification in eukaryotic cells is the addition of N6-methyladenosine (m6A) to RNA, which plays a critical role in regulating RNA stability and translation co-transcriptionally. These modifications are reversibly catalyzed by m6A methyltransferases (writers), demethylases (erasers), and utilized by m6A-binding proteins (readers). The hepatitis E virus (HEV) has a single-stranded, positive-sense (+) RNA genome that undergoes cap-dependent translation. However, the host factors involved in the replication cycle of HEV, particularly RNA modifications that occur during viral replication, remain poorly understood. This study aims to explore the roles of m6A writers, readers, and erasers in the context of HEV infection. To assess the impact of m6A RNA modifications on HEV infection, we administered the methyltransferase METTL3 inhibitor STM2457 to HEV-infected cells in a dose-dependent manner, with subsequent screening for virus-positive cells using fluorescence microscopy. Additionally, HEV replicon-transfected cells were treated with the inhibitor to evaluate effects on viral replication via luciferase assay. Our findings indicate that inhibiting m6A methylation through the use of STM2457 disrupts infection with the human-derived HEV-3 strain Kernow-C1/p6 at an EC50 of ~ 10 nM. However, viral replication remains unaffected when in vitro transcribed RNA is transfected by electroporation. Moreover, the antiviral efficacy of STM2457 was confirmed in primary human hepatocytes, demonstrating an 80% reduction in infection at a 10 µM drug concentration. These findings were further validated by siRNA knockdown experiments, which demonstrated that the depletion of the m6A writer METTL3 and METTL16 by siRNAs decreased HEV infections by 41% and 12%, respectively. In contrast, depletion of writer proteins METTL14 and WTAP as well as the reader protein YTHDF3 and the eraser FTO increased HEV infectivity. In conclusion, our study identified m6A methylation as a component of HEV biology and suggests that it represents a promising target for antiviral interventions.