The secretome of mesenchymal stromal cells (MSCs) has emerged as a promising cell-free therapeutic strategy for regenerative medicine and immune modulation. However, its clinical translation remains limited by restricted stability and the short in vivo half-life of its bioactive factors, often requiring repeated administrations. Here, we describe an injectable star–shaped poly(ethylene glycol)–heparin (starPEG–heparin) hydrogel that enables the stable loading and sustained release (up to 14 days) of a lyophilized immunomodulatory MSC secretome (LS). Controlled delivery resulted from the interplay between LS-derived protease-driven hydrogel degradation and bioactive factor affinity to the heparin building block. Release studies showed sustained liberation of regenerative, immunomodulatory, and matrix-modulating factors, including VEGF, PDGF-AA/BB, IL-1Ra, IL-4, IL-10, Gal-9, and TIMP-1, yielding a compositionally balanced release profile over time. Importantly, hydrogel-released LS preserved robust bioactivity for 14 days, inhibiting ConA-induced PBMC proliferation and partially repolarizing M1 macrophages toward an anti-inflammatory phenotype (reduced CD86 and increased CD209/CD163). These results demonstrate that starPEG–heparin hydrogels maintain LS stability and immunomodulatory bioactivity in vitro for up to two weeks, supporting their use as controlled-release matrices for MSC-derived secretome-based approaches.