<p>Raloxifene (RAL) is an established therapeutic agent for hormone-responsive breast cancer, but its clinical utility is limited by poor oral bioavailability and the need for higher doses that may elevate systemic toxicity. To address these limitations, a novel ester conjugate of raloxifene and ibuprofen (IBU), designated RAL-IBU, was synthesized to improve safety while integrating complementary anticancer and anti-inflammatory properties. RAL-IBU was thoroughly characterized using spectroscopic and analytical techniques, and its bioreversibility was assessed through in vitro hydrolysis studies across pH 1.2–7.4 and in simulated gastric and biological fluids. The conjugate remained stable under acidic gastric conditions but underwent accelerated hydrolysis at pH 5.5–7.4 and in simulated biological fluid, indicating pH-dependent cleavage favorable for tumor-associated microenvironments. Permeation studies further supported minimal gastric absorption and enhanced diffusion under cancer-mimicking conditions, suggesting a reduced off-target exposure. Biological evaluation demonstrated that RAL-IBU retained potent cytotoxic activity against MCF-7 breast cancer cells and exhibited sustained anti-inflammatory activity compared to the parent drugs. Reduced hemolytic activity and lower protein binding indicate an improved systemic safety profile and the potential for enhanced bioavailability. In vivo ulcerogenicity studies confirmed markedly lower gastric mucosal injury relative to ibuprofen, underscoring the conjugate’s gastroprotective advantage. Collectively, these findings indicate that RAL-IBU integrates the therapeutic strengths of raloxifene and ibuprofen while mitigating the key limitations associated with each parent molecule. RAL-IBU represents a promising multifunctional oral conjugate with the potential for safer and more effective breast cancer therapy, warranting further pharmacokinetic and mechanistic investigations.</p> Graphical Abstract <p></p>