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<i>Perilla frutense</i> var. <i>acuta</i> (Lamiaceae) has been used to treat indigestion, asthma, and allergies in traditional medicine. In this study, luteolin 7-<i>O</i>-diglucuronide (<b>1</b>), apigenin 7-<i>O</i>-diglucuronide (<b>2</b>), and rosmarinic acid (<b>3</b>) were isolated from the leaves of <i>P. frutescens</i> var. <i>acuta</i> through various chromatographic purification techniques. Several approaches were used to investigate the anti-inflammatory activity of the constituents (<b>1</b>–<b>3</b>) and their working mechanisms. In silico docking simulation demonstrated that <b>1</b>–<b>3</b> would work as a PPAR-α/δ/γ agonist, and in vitro PPAR-α/δ/γ transcriptional assay showed that the <i>Perilla</i> water extract (PWE) and <b>3</b> increased PPAR-α luciferase activity (1.71 and 1.61 times of the control (PPAR-α + PPRE, <i>p</i> < 0.001)). In the NF-κB luciferase assay, <b>1</b> suppressed NF-κB activity the most (56.83% at 5 µM; 74.96% at 10 µM; 79.86% at 50 µM). In addition, <b>1</b> and <b>2</b> inhibited the mRNA expression of NF-κB target genes, including <i>Il6</i>, <i>Mcp1</i>, and <i>Tnfa</i>, at 50 µM, and <b>3</b> suppressed the genes at the mRNA level in a dose-dependent manner. We report that <b>1</b> and <b>2</b> exert anti-inflammatory effects through NF-κB inhibition, and the PPAR-α/NF-κB signaling pathway is related to the anti-inflammatory activity of <b>3</b>.