Monascus pigment (MP)-loaded hydrogel (HY) was developed to enhance the survival and function of bone marrow-derived mesenchymal stem cells (BMSCs) for treating heart failure (HF). The hydrogel, based on Schiff base cross-linked oxidized hyaluronic acid (OHA) and dopamine-modified hyaluronic acid (HADop), was combined with MP nanoparticles (PPM) to improve the adverse microenvironment in HF. PPM exhibited ROS-scavenging and macrophage phenotype-regulating properties, enhancing BMSC survival and activity in HF conditions. The hydrogel demonstrated biocompatibility, injectability, and tissue adhesion, and synergized with PPM to improve cardiac function in rats. BMSCs encapsulated in HY with PPM showed increased retention and survival, reduced apoptosis, and enhanced secretory functions. Animal studies confirmed that HY@PPM and HY@PPM&BMSCs effectively promoted blood vessel growth, reduced fibrosis, and mitigated ventricular remodeling. PPM reduced oxidative stress, decreased cardiomyocyte apoptosis, and improved the microenvironment, enhancing BMSCs' therapeutic potential. Histological analysis showed improved cardiac structure and reduced fibrosis in treated rats. Apoptosis was significantly reduced in HY@PPM and HY@PPM&BMSC groups compared to the saline group. Cardiac function, as measured by left ventricular ejection fraction (LVEF), improved in HY@BMSC and HY@PPM&BMSC groups, with HY@PPM&BMSCs showing the most significant improvement. These results suggest that HY@PPM and HY@PPM&BMSCs offer promising therapeutic strategies for HF treatment by enhancing BMSC survival, reducing oxidative stress, and improving cardiac function.Monascus pigment (MP)-loaded hydrogel (HY) was developed to enhance the survival and function of bone marrow-derived mesenchymal stem cells (BMSCs) for treating heart failure (HF). The hydrogel, based on Schiff base cross-linked oxidized hyaluronic acid (OHA) and dopamine-modified hyaluronic acid (HADop), was combined with MP nanoparticles (PPM) to improve the adverse microenvironment in HF. PPM exhibited ROS-scavenging and macrophage phenotype-regulating properties, enhancing BMSC survival and activity in HF conditions. The hydrogel demonstrated biocompatibility, injectability, and tissue adhesion, and synergized with PPM to improve cardiac function in rats. BMSCs encapsulated in HY with PPM showed increased retention and survival, reduced apoptosis, and enhanced secretory functions. Animal studies confirmed that HY@PPM and HY@PPM&BMSCs effectively promoted blood vessel growth, reduced fibrosis, and mitigated ventricular remodeling. PPM reduced oxidative stress, decreased cardiomyocyte apoptosis, and improved the microenvironment, enhancing BMSCs' therapeutic potential. Histological analysis showed improved cardiac structure and reduced fibrosis in treated rats. Apoptosis was significantly reduced in HY@PPM and HY@PPM&BMSC groups compared to the saline group. Cardiac function, as measured by left ventricular ejection fraction (LVEF), improved in HY@BMSC and HY@PPM&BMSC groups, with HY@PPM&BMSCs showing the most significant improvement. These results suggest that HY@PPM and HY@PPM&BMSCs offer promising therapeutic strategies for HF treatment by enhancing BMSC survival, reducing oxidative stress, and improving cardiac function.