Polyhedral oligomeric silsesquioxanes (POSS) represent the new frontier in hybrid materials science and engineering, because of their well-defined nanostructure and unique dual nature combining material properties from both inorganic siloxane cage and organic groups at the periphery. Recent advances in synthetic chemistry, combined with the controlled radical polymerization techniques, have significantly influenced the construction of POSS soft gel as emerging biomaterials and beyond. In this Review, the most recent developments in the design strategies of POSS-based hybrid soft gels are presented, with respect to different functions of architectural POSS, including POSS as a crosslinker, end-cap polymer chain, pendent group, etc. In addition, the insights into the uniqueness of POSS in microstructure and their different organic substituents in the enhancement of the hydrogel performance are illustrated. These sophisticated materials with multiple functions, oriented toward advanced therapeutic applications, are further summarized into several active domains in controlled drug delivery, 3D cell culture, tissue engineering, and wound healing. The recent new applications of using POSS hybrid soft gel in environmental health are also summarized in this Review. Finally, perspectives and challenges related to the further advancement of POSS-based hybrid soft gel materials are discussed.