We recently reported on a bioactive HA functionalized with a water‐soluble MMPI, characterized by: 1) an increased resistance to hyaluronidase degradation, 2) MMP inhibition properties, and3) the ability to prevent dehydration of corneal epithelial cells in vivo.[26] Moving a step forward, herein we report on an innovative bioresponsive HA‐based hydrogel (namely, HA‐MMPI) obtained by cross‐linking HA with a branched MMP inhibitor, and on the capacity of HA‐MMPI to inhibit MMP‐2 expression in glioblastoma environment and to reduce tumor cells migration. This evidence concerns the gene MMP2 and neoplasm.