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Ovarian cancer is known as the second leading cause of gynecologic cancer-associated deaths in women worldwide. Developing new and effective compounds to alleviate chemoresistance is an urgent priority in ovarian cancer. Here, we aimed to reveal the biological function and underlying mechanisms of phellopterin, a naturally sourced ingredient of Angelica dahurica, in ovarian cancer progression as well as evaluate the therapeutic potential of phellopterin in ovarian cancer patients. In this investigation, we found that phellopterin mitigated DNA replication and induced cell cycle arrest, apoptosis, and DNA damage, attenuating cell proliferation and chemoresistance of ovarian cancer. Interestingly, bioinformatics analyses of data from our RNA sequencing and The Cancer Genome Atlas ovarian cancer dataset suggested that phellopterin presented anti-cancer activities in ovarian cancer cells by modulating signals affecting ovarian cancer progression and identified phellopterin as a potential compound in improving ovarian cancer patients' prognosis. In addition, the C-Type Lectin Domain Containing 5A (CLEC5A) was demonstrated as a downstream effector of phellopterin and involved in a positive PU.1/CLEC5A/PI3K-AKT feedback loop. Interestingly, phellopterin might inactivate the positive feedback circuit to suppress ovarian cancer progression. Collectively, our investigation revealed that phellopterin mitigated ovarian cancer proliferation and chemoresistance through suppressing the PU.1/CLEC5A/PI3K-AKT feedback loop, and predicted phellopterin as a new and effective cytotoxic drug and CLEC5A as a potential target for the treatment of ovarian cancer. • Phellopterin presented cytotoxic activities in ovarian cancer cells. • Phellopterin attenuated ovarian cancer proliferation and chemoresistance. • Phellopterin inactivated the PU.1/CLEC5A/PI3K-AKT feedback loop. • Phellopterin was predicted as an effective cytotoxic drug in ovarian cancer. [ABSTRACT FROM AUTHOR]