Harnessing the potential of hydrogel-based localized drug delivery systems holds immense promise for mitigating the systemic side effects associated with conventional cancer therapies. However, the development of such systems demands the fulfillment of multiple stringent criteria, including injectability, biocompatibility, and controlled release. Herein, we present an ultra-small peptide-based hydrogel for the sustained and targeted delivery of doxorubicin in a murine model of breast cancer. The hydrogel evades dissolution and remains stable in biological fluids, serving as a reliable drug reservoir. However, it specifically reacts to the high levels of glutathione (GSH) in the tumor microenvironment and releases drugs in a controlled manner over time for consistent therapeutic benefits. Remarkably, administration of a single dose of doxorubicin-loaded hydrogel elicited superior tumor regression (approximately 75% within 18 days) compared to conventional doxorubicin treatment alone. Furthermore, the persistent presence of the drug-loaded hydrogel near the tumor site for up to 18 days after administration highlights its enduring effectiveness. There is great clinical potential for this localized delivery strategy because of the minimal off-target effects on healthy tissues. Our findings underscore the efficacy of this smart peptide-hydrogel platform and pave the way for developing next-generation localized drug delivery systems with enhanced therapeutic outcomes in cancer treatment.