Multiple pesticides often coexist in soil, potentially leading to interactions among their components, these may detrimentally impact soil organisms. This study assessed the potential risks posed by simultaneous exposure to atrazine (ATR) and phoxim (PHO) on enzyme and transcription levels in earthworms (Eisenia fetida). The results revealed that ATR exhibited higher acute toxicity towards E. fetida compared to PHO, and their combined exposure resulted in a synergistic acute effect. Furthermore, low concentration combined exposure significantly stimulated catalase (CAT), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) activities, which lead to more severe oxidative damage. Elevated expression levels of translationally controlled tumor protein (tctp) and calreticulin (crt) genes were observed in most exposed groups compared to the control. The synergistic effects of ATR and PHO on earthworms observed in this study may pose ecological risks to the soil ecosystem; thus, more attention should be paid to the joint effects of different pesticides.