Multiple drugs-loaded electrospun composite nanofibrous scaffolds have attracted much interest as drug delivery vehicles for the treatment of tissue defect after tumor resection. In this study, a novel mesoporous ZnO/poly(lactic-co-glycolic acid)/gelatin (mZnO/PLGA/GE) electrospun composite fiber encapsulated with both hydrophilic drug (doxorubicin hydrochloride, DOX) and hydrophobic drug (camptothecin, CPT) is fabricated. mZnO is firstly used to encapsulate DOX. Then, the DOX-loaded mZnO (DOX@mZnO) and CPT were mixed with PLGA/GE solution to fabricate electrospun hybrid nanofibers. The in vitro release results demonstrated that the CPT in the composite fibers presented a fast release, while DOX showed a sustained release behavior. The cell cytotoxicity test indicated that the composite nanofiber with two drugs showed strong antitumor efficacy against HepG-2 cells. Moreover, the addition of GE increased the hydrophilicity of the composite fibers. More importantly, the incorporated of mZnO within the PLGA/GE nanofibers cannot only significantly reduce the burst release of DOX, but also improve the mechanical durability of the composite nanofibers. Thus, the composite nanofibers could be a versatile drug delivery system encapsulated with both hydrophilic and hydrophobic anticancer drugs as implantable scaffolds for potential postsurgical cancer treatment.