PurposeAlthough paclitaxel is a promising first-line chemotherapeutic drug for ovarian cancer, acquired resistance to paclitaxel is one of the leading causes of treatment failure, limiting its clinical application.Asparagus officinalishas been shown to have anti-tumorigenic effects on cell growth, apoptosis, cellular stress and invasion of various types of cancer cells and has also been shown to synergize with paclitaxel to inhibit cell proliferation in ovarian cancer.MethodsHuman ovarian cancer cell lines MES and its PTX-resistant counterpart MES-TP cell lines were used and were treated withAsparagus officinalisand paclitaxel alone as well as in combination. Cell proliferation, cellular stress, invasion and DMA damage were investigated and the synergistic effect of a combined therapy analyzed.ResultsIn this study, we found thatAsparagus officinaliscombined with low-dose paclitaxel synergistically inhibited cell proliferation, induced cellular stress and apoptosis and reduced cell invasion in paclitaxel-sensitive and -resistant ovarian cancer cell lines. The combined treatment effects were dependent on DNA damage pathways and suppressing microtubule dynamics, and the AKT/mTOR pathway and microtubule-associated proteins regulated the inhibitory effect through different mechanisms in paclitaxel-sensitive and -resistant cells.ConclusionThese findings suggest that the combination ofAsparagus officinalisand paclitaxel have potential clinical implications for development as a novel ovarian cancer treatment strategy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-022-04276-8.