Background: It is well established that renal cell carcinoma (RCC) is an obesity-associated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism. Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immunohistochemistry. Assays with RCC cell lines were used to examine the signal transduction pathways of adiponectin in RCC. Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sensitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor interactions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3β and β-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-κB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin. Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy.