Ferroptosis, a newly iron-dependent form of cell death, is often accompanied by the damage of membrane lipid peroxide. Recently, the ferroptosis inducer erastin has been reported to exhibit potential anti-cancer activities. The aim of this study was to investigate the effects of SRSF9 on the sensitivity of colorectal cancer (CRC) to erastin and explore the underlying molecular mechanism. Short hairpin RNAs (shRNAs) or SRSF9 overexpression vector (SRSF9-OE) was transfected into erastin-induced human CRC cells to inhibit or overexpress SRSF9. Results showed that SRSF9 inhibition promoted the cell death induced by erastin, conversely, SRSF9 overexpression augmented the resistance to erastin-induced death in human CRC cells. SRSF9 decreased lipid peroxide damage which was a key event during erastin-induced ferroptosis in human CRC cells. Furthermore, we found that SRSF9 inhibition increased erastin-induced ferroptosis by downregulating GPX4 level. In an In vivo study, SRSF9 shRNA or SRSF9-OE stably transfected human CRC cells were subcutaneously injected into the right flank of nude mice. SRSF9 overexpression partly abolished the tumor growth inhibition and ferroptosis induced by erastin. Our data indicated SRSF9’s regulation of GPX4 as an essential mechanism driving CRC tumorigenesis and resistance of erastin-induced ferroptosis. This molecular mechanism may provide a novel method for improving the sensitivity of CRC to erastin.