Bcl-xL is a well-characterized target gene of cancer. DT2216, a selective proteolysis-targeting chimera (PROTAC) has been developed for targeting Bcl-xL without causing pronounced thrombocytopenia. However, like most PROTACs, DT2216 has its intrinsic limitations such as low permeability, poor solubility, low bioavailability, and nonspecific biological distribution. In this study, a novel nanoliposome (NP)-encapsulated DT2216 (DT@NPs) was developed and the anti-cancer effects and safety of DT@NPs in vitro and in vivo were assessed. The DT@NPs had notable cytocompatibility in normal cells and good bioavailability in cancer cells. Compared with DT2216, DT@NPs exhibited an enhanced ability to degrade Bcl-xL in two cervical cancer cell lines (C33A and SiHa) and a triple-negative breast cancer cell line (MDA-MB-231), resulting in notably enhanced cytotoxicity for cancer cells, in particular, for MDA-MB-231. The apoptosis, colony formation, and wound healing assays showed that DT@NPs had a stronger effect on inducing apoptosis, suppressing colony formation, and inhibiting cellular migration than DT2216. Moreover, a notable inhibition of DT@NPs on tumor growth was observed in the tumor-bearing murine model. A high accumulation of Cy5-labeled DT@NPs in the tumor indicated that DT@NPs had a good biodistribution in vivo. DT@NPs showed stronger inhibition of tumor growth than DT2216 by enhancing the Bcl-xL degradation and apoptosis. The comprehensive safety assessments in histology, blood cell count, and the biochemical indicators of peripheral blood suggested that DT@NPs showed no appreciable on-target toxicities and side effects. In conclusion, nanoliposomal Bcl-xL targeted PROTAC enhanced anti-cancer effects on cervical and breast cancer without causing on-target toxicities.