Breast cancer is the most frequently diagnosed cancer type among women. Chemotherapeutic agents are widely used in the treatment of breast cancer, but acquired drug resistance limits their effectiveness. Therefore, there is a continuing need for more effective treatment approaches with fewer side effects. Caffeine is one of the naturally occurring xanthines in coffee beans, caffeine is the most commonly used psychoactive substance worldwide. Numerous studies have highlighted the health benefits of coffee consumption, including reducing the risk of heart disease and certain cancers. Docetaxel is a second-generation antineoplastic agent of the taxane family and is widely used in the treatment of numerous cancers such as breast cancer. Herein, we evaluated the effect of caffeine and its combination with docetaxel on MCF-7 breast cancer cells. To test the effect of caffeine and its combination with docetaxel, we evaluated the autophagy, ubiquitin-proteasome system (UPS), unfolded protein response (UPR) signaling and apoptosis-related protein levels by immunoblotting. Cell viability was measured by WST-1 method. Morphological alterations in cells were evaluated in microscopical examinations. We found that caffeine remarkably induced UPR signaling, accelerated autophagic flux, and UPS-dependent protein turnover. Co-administration of caffeine and docetaxel strongly diminished the viability of MCF-7 cells by expanding the cytotoxic effect of docetaxel through accelerating the UPS-dependent protein turnover, induction of UPR and autophagy and apoptotic protein levels in a dose-dependent manner. Our results suggest that caffeine supplementation with docetaxel may expand the chemotherapeutic efficiency of docetaxel in breast cancer.