Ovarian cancer (OV) is one of the most common female malignancies with high morbidity and mortality, but its mechanism is not fully understood. The circadian clock is involved in the regulation of the immune system and the tumor microenvironment, regulating biological processes and behaviors in multiple ways. Circadian rhythm disorders are considered a risk factor for tumorigenesis. Multi-omics analysis was performed to comprehensively illustrate the roles of circadian clock genes in OV, we found that most of circadian clock genes undergo epigenetic alterations in OV and are strongly correlated with overall and progression-free patient survival. These clock genes are mainly involved in the inhibition of Apoptosis pathway, Cell Cycle pathway and DNA Damage Response pathway, as well as the activation of RAS/MAPK pathway and RTK pathway. Drug sensitivity model indicate that the expression of core clock genes may associate with drug resistance. Further, immune infiltrates analysis shows that different mutant forms of core genes can not only suppress immune infiltration, but also affect clinical outcome of ovarian cancer patients. Overall, our results may provide novel insights for the potential selection of immunotherapeutic targets. Copyright © 2021 Elsevier B.V. All rights reserved.