This study investigated the antibacterial potential of locally abundant plant materials in the Philippines, focusing on calamansi peel (Citrus microcarpa) agro-waste and lemongrass (Cymbopogon citratus) leaves as sustainable alternatives to synthetic antibiotics amid rising antimicrobial resistance. Despite known individual antimicrobial properties, limited evidence exists on their combined effects against Escherichia coli. The study aimed to determine and compare the antibacterial activity of individual and combined ethanol extracts and assess whether their interaction is synergistic or indifferent. A quantitative experimental design was employed using the Kirby–Bauer disk diffusion method. Ethanol extracts of calamansi peels, lemongrass leaves, and their combination were tested against a standardized E. coli culture with positive and negative controls, each in triplicate. Zones of inhibition (mm) were measured and analyzed using mean, standard deviation, one-way ANOVA, and Tukey’s HSD at a 0.05 significance. The results revealed mean zones of inhibition of 17.33 mm for calamansi ethanol extract, 18.00 mm for lemongrass ethanol extract, and 18.33 mm for the combined ethanol extract. Although the combined extract exhibited the highest mean inhibition, statistical analysis indicated no significant difference among the three plant treatments, suggesting an indifferent interaction rather than synergistic effect. The findings highlight the potential of calamansi peels and lemongrass leaves as natural antibacterial agents and support their application in eco-friendly disinfectant formulations. Future studies should determine minimum inhibitory concentrations and conduct phytochemical profiling to strengthen product development.