A novel poly(lactic-co-glycolic acid) (PLGA)/ZnO electrospun composite fibers encapsulated with both hydrophilic drug (doxorubicin hydrochloride, DOX) and hydrophobic drug (camptothecin, CPT) were fabricated via electrospinning method. Primarily, the ZnO was decorat with F127 and then used to encapsulate DOX. Finally, the DOX-loaded ZnO(DOX@ZnO) and CPT were mixed with PLGA solution to fabricate electrospun hybrid nanofibers. The in vitro release results demonstrated the composite fibers decreased the burst release and increased the time of release, which showed a long-term and sustained release. The cell cytotoxicity test demonstated that the composite nanofiber with two drugs showed stronger antitumor efficacy against HepG-2 cells than the nanofiber with single drug. Thus, the composite nanofibers with two anticancer drugs could be a versatile drug delivery system as local implantable scaffolds for potential postsurgical cancer treatment.