Exogenously delivered mesenchymal stromal cells (MSCs) are therapeutically beneficial owing to their paracrine effect; they secrete various cytokines, nucleic acids, and proteins. Multiple bioengineering techniques can help MSC cultures to release secretomes by providing stem cell niche-like conditions (both structurally and functionally). Various scaffolds mimic the natural extracellular matrix (ECM) using both natural and synthetic polymers, providing favorable environments for MSC proliferation and differentiation. Depending on material properties, either topographically or elastically structured scaffolds can be fabricated. Three-dimensional scaffolds have tunable substrate rigidities and structures, aiding MSC cultivation. Decellularized ECM-derived hydrogels are similar to the natural ECM, thus improving the paracrine effects of MSCs. Here, we discuss recent research on the application of scaffolds to maximize the immunomodulatory function of MSCs.