Propofol (Pro) confers protection against renal ischemia/reperfusion (rI/R) injury through incompletely characterized mechanisms. Since Pro has shown net anti-inflammatory properties as part of its beneficial effects, we examined the potential role of Pro in the modulation of macrophage polarization status during both rI/R injury in vivo and exposure of cultured peritoneal macrophages (PMs) to hypoxia/reoxygenation (H/R). Rats were subjected to 45-min r/IR surgery or a sham procedure and administered PBS (vehicle) or Pro during the ischemia stage. Pro administration attenuated rI/R-induced kidney damage and renal TNF-α, IL-6, and CXCL-10 expression. Enhanced macrophage M2 polarization, evidenced by reduced iNOS and increased Arg1 and Mrc1 mRNA levels, was further detected after Pro treatment both in the kidney, after rI/R in vivo, and in H/R-treated PMs. Pro administration also repressed phosphorylated signal transducer and activator of transcription 1 (p-STAT1) and increased p-STAT3, p-STAT6, and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA levels in H/R-exposed PMs. Importantly, siRNA-mediated PPARγ silencing repressed Pro-mediated STAT3 activation in PMs and restored proinflammatory cytokine levels and prevented macrophage M2 marker expression in both rI/R-treated rats and cultured PMs. These findings suggest that Pro confers renoprotection against rI/R by stimulating PPARγ/STAT3-dependent macrophage conversion to the M2 phenotype.