Secondary lymphedema is a debilitating chronic tissue swelling in a limb caused by inadequate interstitial fluid drainage due to dysfunctional lymphatic vessels. Pathological enlargement of small lymphatics contributes to lymphatic dysfunction in secondary lymphedema, but molecular mechanisms driving this remodeling are unclear. Here, using a surgical mouse model of secondary lymphedema and whole-genome microarray, we identified the transcript for insulin-like growth factor binding protein 5 (IGFBP5), a negative regulator of insulin-like growth factor (IGF) signaling, as the most profoundly down-regulated in lymphedematous tissue. Notably, IGF signaling via IGF1 receptor (IGF1R) was previously shown to promote lymphatic remodeling. We therefore targeted IGF1R in the mouse model using the small molecule IGF1R inhibitor linsitinib. Linsitinib restricted enlargement of small lymphatics and tissue swelling during lymphedema development, likely by inhibiting IGF1R-driven vascular endothelial growth factor-C (VEGF-C) synthesis by macrophages. Importantly, linsitinib profoundly reduced tissue swelling in mice with chronic lymphedema suggesting IGF signaling as a therapeutic target for this disease.