Management of lymph node metastasis (LNM) by conventional modalities such as radiotherapy and systemic chemotherapy exhibit limited LNM selectivity and therefore can cause off-target adverse events. While development of LNM-specific drug delivery systems has tremendous potential to provide a safer treatment modality and improve cancer treatment, precise assessment of therapeutic efficacy and implications has been challenging due to lack of a suitable preclinical model. Here, we established an experimental LNM model in mice by directly seeding cancer cells into a lymph node (LN), which developed spontaneous LNM-borne distant metastasis (DM) in the absence of a primary tumor. In the model, early, but not late, management of LNM before thereof tumor cells systemically disseminated could confer significant survival benefit, which suggests that time to LNM management is critical. Systematic comparative assessment of various local drug delivery systems revealed that a micellar formulation could achieve highly LNM-specific delivery of a chemotherapeutic agent, which was superior to systemic chemotherapy, effective at a very low dose, and safe. This study suggests not only that the experimental LNM model provides a useful preclinical model to study LNM management and its therapeutic implications but also that micelles are a promising drug delivery system for LNM management via local administration.