Background: Empirically red Piper betle leaf (Piper crocatum Ruiz and Pav) is used as a natural antiseptic, and it is proved that the ethanol extract of red P. betle leaf ethanol extract provides antimicrobial activity against the airborne pathogen. Aims and Objectives: To investigate and determine the most effective of the lotion formulated with red P. betle leaf ethanol extract against airborne pathogens. Materials and Methods: The plant material in this study was red P. betle leaves that obtained from Bogor Indonesia. The preliminary antimicrobial activity of the extracts at various concentrations was conducted to determine the minimum inhibitory concentration (MIC) of the extract against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. The MIC test was performed using an agar diffusion method with perforation technique. Then, antimicrobial lotions (F1-F3) were formulated in varied concentrations (5, 7.5 and 10% w/w) of red P. betle leaf extracts using different excipients and kept for 28 days at 8°C, 25°C, and 40°C. The physicochemical and microbiological parameters of the lotion formulated were evaluated using standard procedures. Results: MIC range for red P. betle leaf extract was found to be 2.5-5% b/v for all bacteria and 1.25-2.5% b/v for C. albicans. A formulation containing these extracts showed a nonsignificant zone of inhibition for 5%, 7.5%, and 10% of which 10% showed maximum zone of inhibition (ranging from 11.23 to 11.83 mm). All of the lotion formulated were stabil for the physicochemical parameters of evaluation. Conclusion: The F2 lotion formula had good pharmaceutical properties and potential antimicrobial activity.