Colorectal cancer (CRC) is the second most common cancer‐related deaths throughout the world. Ferroptosis is a recently regulated form of cell death, lately gains attention. MicroRNA‐15a‐3p (miR‐15a‐3p) plays a regulatory role in various kinds of cancers. However, the role of miR‐15a‐3p in cellular ferroptosis is still unclear. Here, we aimed to clarify whether miR‐15a‐3p could regulate the ferroptosis of CRC. Here we identified miR‐15a‐3p positively regulates ferroptosis via directly targeting glutathione peroxidase glutathione peroxidase 4 (GPX4) in CRC. Overexpression of miR‐15a‐3p repressed GPX4 through binding to the 3′‐untranslated region of GPX4, resulting in increased reactive oxygen species level, intracellular Fe2+ level, and malondialdehyde accumulation in vitro and in vivo. Correspondingly, suppression of miR‐15a‐3p reduced the sensitivity of CRC cells to erastin and GPX4. Taken together, these data demonstrate that miR‐15a‐3p regulates ferroptosis through targeting GPX4 in CRC cells, illustrating the novel role of microRNA in ferroptosis.