Oxidative stress and chronic inflammation are closely linked to various diseases. However, previous studies have demonstrated that plant extracts could prevent and alleviate these adverse outcomes. Piper betle Linn. (Piper betle L.) is a cosmopolitan plant that belongs to the Piperaceae family, whose leaves are edible and possess several health benefits. This study sought to characterize the anti-inflammatory and antioxidant effects of a methanol extract of Piper betle L. leaves and stems (MPBLLS). MPBLLS was found to have a dose-dependent radical scavenging effect, as demonstrated by the 2,2-diphenyl-1-picrylhydrazyl assay. Additionally, MPBLLS inhibited the lipopolysaccharide (LPS)-stimulated production of nitric oxide and prostaglandin E₂ by reducing the expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophages without affecting cell viability. Furthermore, our findings suggested that the inhibitory effects of MPBLLS on pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 were due to the inhibition of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in LPS-treated RAW 264.7 macrophages. MPBLLS and hydroxychavicol, a major constituent of MPBLLS, suppressed LPS-induced translocation of NF-κB p65 from cytoplasm to nucleus. Interestingly, MPBLLS increased nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels and transcription levels of Nrf2 target genes in a dose-dependent manner. Collectively, our findings suggest that MPBLLS could serve as a basis for the development of novel orally-administered therapies due to its inhibitory effects on oxidative and inflammatory stress. DATA AVAILABILITY: The data presented in this study are available on request from the corresponding author.