Zearalenone (ZEA), a toxic substance produced by Fusarium fungi, accumulated in cereals grain and animal feed, causes injury to humans and animals. ZEA can induce obvious reproductive toxicity with the ovarian granulosa cells (GCs) as the main target. However, the study on exploring the protective compounds against ZEA-induced mouse primary ovarian GCs damage remains less. In the current study, the protective effect of 20 compounds derived from traditional Chinese medicines (TCMs) on the injury of mouse GCs caused by ZEA were evaluated using MTT assay and the cell morphology. Our results showed that chlorogenic acid (250, 500, and 1000 μg/mL) significantly suppress ZEA-induced GCs death. Western blot analysis suggested chlorogenic acid could rescue the up-regulated apoptosis of GCs induced by ZEA via attenuating the protein expression of cleaved caspase-3, the ratio of Bax/Bcl-2 and cleaved-PARP. Our results provide strong evidence that chlorogenic acid warrants further optimization for more potent and safer compounds for against the ZEA lead toxicity to humans and animals.