This study investigated the inhibitory effects of matrix metallopeptidase 2 (MMP2)-responsive curcumin-loaded nanoparticles on glioblastoma multiforme (GBM), and elucidated their underlying mechanisms. The methods employed included the Cell Counting Kit-8 viability assay, colony formation assay, flow cytometry for apoptosis analysis, wound healing migration assay, quantitative real-time polymerase chain reaction, western blotting for gene expression profiling, mitochondrial function assessment, and in vivo antitumor efficacy evaluation. Curcumin significantly reduced the viability, proliferation, and migratory capacity of murine glioma cells (GL261). It also induced apoptosis, disrupted mitochondrial function, and increased reactive oxygen species levels. Notably, curcumin upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression while inhibiting signal transducer and activator of transcription 3 (STAT3) activation. The synthesized MMP2-responsive curcumin nanoparticles (Cur-NPs) effectively suppressed tumor growth and prolonged survival in a GBM mouse model. These data suggest that curcumin inhibits STAT3 activity via an Nrf2-dependent mechanism. This study advances our understanding of the mechanism of action of curcumin and suggests potential avenues for the development of targeted therapies for GBM.