In cervical cancer (CC), the efficacy of chemotherapy is often hindered by the development of paclitaxel (PTX) resistance, even in patients who initially responded to chemotherapy. However, the mechanisms underlying PTX resistance in CC patients remain unclear. In this study, we uncover a unique role played by CENPU (centromeric protein U, also known as PBIP1/KLIP1/CENP-50/MLF1IP) in association with paclitaxel resistance in CC cells. First, we established paclitaxel-resistant cell lines from Hela and SiHa cells (designated as Hela/PTX and SiHa/PTX) and confirmed their resistance by determining the half-maximal inhibitory concentration (IC50) values and assessing cell viability. The results demonstrated that Hela/PTX and SiHa/PTX cells exhibited an elevated IC50 and enhanced cell proliferation, accompanied by a decrease in apoptosis. Subsequently, si-CENPU was used to silence CENPU in Hela/PTX and SiHa/PTX cells, which led to a reduction in cell viability and an increase in cell apoptosis, indicating that the silencing of CENPU mitigated paclitaxel resistance in Hela/PTX and SiHa/PTX cells. Furthermore, CENPU knockdown suppressed Forkhead box M1 (FOXM1) and Adenosine Triphosphate (ATP) binding cassette subfamily C member 5 (ABCC5) expression in Hela/PTX and SiHa/PTX cells. Interestingly, the alleviating effects of CENPU silencing on paclitaxel resistance in CC cells were compromised when FOXM1 levels were supplemented, indicating that CENPU knockdown could attenuate PTX resistance by downregulating the FOXM1/ABCC5 signaling pathway. In conclusion, our study reveals an elevated expression of CENPU in paclitaxel-resistant CC (Hela/PTX and SiHa/PTX) and demonstrates that the knockdown of CENPU can mitigate paclitaxel resistance in CC cells by deregulating the FOXM1/ABCC5 signaling pathway.