Inflammation is a physiological defense mechanism of the body in response to various pathological stimuli, including tissue injury, infection, and exposure to foreign substances. This process is characterized by clinical manifestations such as edema, pain, redness, and increased local tissue temperature. The long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause several adverse effects, thereby encouraging the exploration of natural products as alternative anti-inflammatory agents. Red betel leaf (Piper crocatum) and Chinese betel leaf (Peperomia pellucida L.) are medicinal plants containing bioactive secondary metabolites, including flavonoids, alkaloids, and tannins, which are associated with anti-inflammatory activity. This study aimed to compare the anti-inflammatory activity of ethanol extracts from red betel leaf and Chinese betel leaf against carrageenan-induced paw edema in mice (Mus musculus) based on two experimental studies with comparable extraction methods, anti-inflammatory assays, and statistical analyses. The evaluated parameters included extract yield, phytochemical screening, edema measurement using a caliper and plethysmometer, and statistical analysis results. The findings showed that the ethanol extract yield of red betel leaf was 26.57%, while Chinese betel leaf extract was 24.10%. Phytochemical screening revealed that both extracts contained alkaloids, flavonoids, and tannins. Based on caliper measurements, the optimal anti-inflammatory dose of red betel leaf extract was 250 mg/kg body weight, whereas Chinese betel leaf extract showed the optimum dose at 200 mg/kg body weight. Plethysmometer measurements indicated optimal doses of 200 mg/kg body weight for red betel leaf extract and 175 mg/kg body weight for Chinese betel leaf extract. Statistical analysis demonstrated significant differences among treatment groups (p < 0.05). Both ethanol extracts exhibited potential as natural anti-inflammatory agents, although their effectiveness varied depending on dosage and edema measurement methods.