ABSTRACTCold atmospheric plasma‐activated hydrogel (PAH) exhibits excellent loading and slow‐release capacity for plasma‐generated reactive species. In this study, plasma‐activated pluronic F127 hydrogel (PAH‐PF127) was obtained using surface dielectric barrier discharge (SDBD), and the anticancer effects of PAH‐F127 synergies with the clinical drug paclitaxel (PTX) were investigated. The results indicated that PAH‐PF127 could load plasma‐generated long‐lived reactive species efficiently, and in vitro research revealed that PAH‐PF127 exerts significant anticancer effects by inducing intracellular oxidative stress, and synergies with 50 μg/mL (low‐dose) PTX could easily replace 200 μg/mL (high‐dose) PTX alone. These results suggested that PAH‐PF127 has the potential to address the toxic side effects of high‐dose drugs and expand the application of plasma technology in anticancer treatment.