Abstract Optogenetics and photonic technologies are changing the future of medicine. To implement light-based therapies in the clinic, patient-friendly devices that can deliver light inside the body while offering tunable properties and compatibility with soft tissues are needed. Here extrusion printing of degradable, hydrogel-based optical waveguides with optical losses as low as 0.1 dB cm−1 at visible wavelengths is described. Core-only and core-cladding fibers are printed at room temperature from polyethylene glycol (PEG)-based and PEG/Pluronic precursors, and cured by in situ photopolymerization. The obtained waveguides are flexible, with mechanical properties tunable within a tissue-compatible range. Degradation times are also tunable by adjusting the molar mass of the diacrylate gel precursors, which are synthesized by linking PEG diacrylate (PEGDA) with varying proportions of DL-dithiothreitol (DTT). The printed waveguides are used to activate photochemical and optogenetic processes in close-to-physiological environments. Light-triggered migration of cells in a photoresponsive 3D hydrogel and drug release from an optogenetically-engineered living material by delivering light across >5 cm of muscle tissue are demonstrated. These results quantify the in vitro performance, and reflect the potential of the printed degradable fibers for in vivo and clinical applications.