This study aimed to identify the anti-inflammatory activity and mechanism of Rubus suavissimus S. Lee leaf extract in a mouse model with LPS-induced systemic low-grade chronic inflammation. The persistent LPS administration to mice increased intestinal permeability and induced a systemic low-grade chronic inflammation, which increases the potential risk of developing metabolic disorders. Supplementation of Rubus suavissimus S. Lee leaf extract suppressed the secretion of pro-inflammatory mediators, TNF-α, IL-6, and MCP-1, and promoted the secretion of anti-inflammatory mediator, adiponectin by increasing protein expression of PPAR-γ. Rubus suavissimus S. Lee leaf extract decreased intestinal permeability by modulating the gene expression of tight junction proteins, prevented macrophage infiltration, and prevented the insulin resistance by restoring insulin sensitivity and increasing the protein expression of IRS-1. This study has demonstrated that Rubus suavissimus S. Lee leaf extract possessed anti-inflammatory and protective effects in preventing systemic low-grade chronic inflammation and inflammation-induced early stage of metabolic disorders.