Abstract Probiotics, recognized for their cost‐effective production, easy storage, and straightforward delivery, are a key focus in developing innovative delivery systems for disease treatment. However, the limited delivery efficacy of probiotics and potential safety issues have hastened their broader application. In this study, a hydrogel encapsulation system is developed to improve the therapeutic efficiency of probiotics through subcutaneous administration. This encapsulation approach is proven to protect the probiotics, thus prolonging their lifetime and enhancing delivery efficiency. Besides, the growth of probiotics is limited within the hydrogel microparticle, which may reduce the adverse effects on the surrounding tissues. This probiotic therapy regimen is demonstrated in Exendin‐4 delivery for diabetic treatment, as well as the delivery of thrombopoietin mimetic peptide for thrombocytopenia treatment. In summary, this system has shown the promising potential of probiotic encapsulation in improving the efficacy and safety of probiotic therapy in various diseases.