Raloxifene hydrochloride (RLX) is a selective estrogen receptor modulator used for treatment and protection against postmenopausal osteoporosis. The drug has been used for protection against breast cancer and more recently, for management of the disease by virtue of its estrogen antagonist action. However, the drug has reduced bioavailability related to low water solubility and first pass metabolism. To surmount these pitfalls, this study aimed at developing and optimizing RLX-loaded semisolid self-nanoemulsifying system (SSNES) with minimized globule size to improve the drug solubility, tumor penetration, and consequently antitumor activity. A simplex lattice mixture design was employed for the formulation and optimization of SSNESs. The mixture components, namely, Compritol® 888 ATO, Tween 20, and polyethylene glycol 200 exhibited significant effect on globule size at P < 0.05. The optimized formulation with globule size of 109.19 ± 2.11 nm showed acceptable thermodynamic stability under stress conditions. Anti-cancer efficacy of the obtained formulation was evaluated in MCF-7 breast cancer cell line. MTT viability assay revealed that RLX-loaded SSNES notably inhibited MCF-7 cell proliferation. Flow cytometry and dual staining with annexin V-FITC/PI were used to assay this anti-proliferative effect and induction of apoptosis, respectively. Cells treated with RLX-loaded SSNES showed significant arrest at G2/M phase associated with significant increase in early/late-stages of apoptotic and necrotic cells. The results exhibited that RLX-loaded SSNES induces apoptosis via the activation of caspase-3 and loss of mitochondrial membrane potential. Accordingly, the proposed SSNES could be regarded as a promising platform for enhancing RLX antitumor activity against breast cancer.