Lymph nodes are secondary lymphoid tissues that play a critical role in filtering the lymph and supporting adaptive immune responses. Surgical resection of LNs, radiation therapy or infections may damage lymphatic vasculature and compromised immune functions. Here, we describe the generation of functional synthetic lympho-organoids (LOs) using LN stromal progenitors and decellularized extra cellular matrix-based scaffolds. We show that upon transplantation at the site of resected LNs, LOs become integrated into the endogenous lymphatic vasculature and efficiently restore lymphatic drainage and perfusion. Upon immunization, LOs support the activation of antigen-specific immune responses, thus acquiring properties of native lymphoid tissues. These findings provide the first proof-of-concept for the development of synthetic lympho-organoids suitable to restore lymphatic and immune cell functions.