© 2020 Elsevier B.V.Breast cancer is the most common type of cancer and it is the second common cause of cancer-related deaths in women. Hormonal therapy is a quite well-tolerated treatment, for estrogen receptor (ER) and progesterone receptor-positive breast cancers. Selective estrogen receptor modulators (SERM) is a specific drug group, structurally different from estrogen, configured as nonsteroidal estrogen with the ability to bind estrogen receptors competitively. They are not readily soluble in biological fluids and have some bioavailability problems. In this study, liposome formulations of tamoxifen and raloxifene were developed with penetration enhancers dimethyl-β-cyclodextrin (DM-β-CD) or sodium taurocholate (NaTC). These formulations were subjected to in vivo and in vitro tests. Raloxifene and DM-β-CD liposomes showed almost 3.5 folds higher permeability coefficients through Caco-2 cell lines. Tamoxifen DM-β-CD liposomes representing particle size with a value of 244.7 ± 8.1 nm (polydispersity index was 0.332, the zeta potential was −14.8 mV and encapsulation efficiency was 45.1%) have shown higher tumor size reduction (92.5%) and therapeutic efficacy (50%). All these results indicate that SERM drug-containing liposomes with a penetration enhancer can be a better therapeutic alternative for oral treatment of breast cancer.