<p>While hydrogel optical fibers hold promises for visceral peripheral optogenetics, their utility is limited by poor tissue adhesion, unstable light delivery, and micromisplacement under physiological motion, leading to off-target illumination. To address these challenges, we developed tissue-adhesive hydrogel optical fibers (TAHOFs) integrating a poly(HEMA) light-guiding core (<i>n</i>_core = 1.429 ± 0.004) with a bioadhesive cladding (<i>n</i>_cladding = 1.343 ± 0.002), achieving dual functionality through refractive index contrast (Δ<i>n</i> = 0.086) and robust tissue integration (11.5 ± 1.8 kPa). This architecture enables efficient optical confinement with low propagation loss (0.534 ± 0.092 dB/cm) while maintaining spatial targeting fidelity under 30% tensile strain. Pancreatic implantation in freely moving ChAT-ChR2 mice demonstrated precise vagal fiber activation, effectively triggering insulin secretion through mechanically and optically stable light delivery. Integrated with subcutaneous continuous glucose monitoring, TAHOFs enabled 3-day glycemic control in diabetic models, showing stable blood glucose reduction and real-time regulation. Chronic implantation demonstrated that TAHOF supports stable in vivo adhesion on the pancreas while maintaining optogenetic function for up to 14 days. The TAHOF uniting high optical efficiency, mechanical compliance, and biological integration, offering an application-specific design strategy for optogenetic neuromodulation in moving animals, particularly mechanically dynamic and anatomically complex organs.</p>