Acute wounds are injuries that occur suddenly to tissues that are prone to the risk of being infected. Therefore, acute wound care must be considered carefully. Piper betle leaf contains flavonoids that have a function in the wound healing process, Manuka honey also contains vitamins that can support the healing phase. The combination of Piper betle L. and manuka honey is made into a spray gel preparation because it has advantages over other topical preparations. The purpose of this study is to see how well a combination wound healing spray gel of Piper betle L. and Manuka honey works on an acute wound in mice. This study uses experimental research with a randomized, matched post-test-only control group design. The formulation taken was maceration extraction from Piper betle L. Simplicia powder with 70% ethanol then evaporated to acquire a concentrated concentrate. Spray gel preparations of a combination of Piper betle L extract and manuka honey were made with a concentration of 1% Piper betle L and Manuka honey, 3% Piper betle L and Manuka honey, and 5% Piper betle L and Manuka honey. Balb/c mice that had full-thickness acute wounds were divided into 7 treatment groups, namely SM1, SM2, SM3, M, KP, B, and D. Mice were treated for 14 days and the wound area ratio was calculated and analyzed by ANOVA. The test results showed a significant difference between groups SM3-M, SM5-M, M-SM3, M-SM5, KP-M, B-SM3, and BM with a significance value below 0.05 (p≤0.05) which proves that the spray gel combination of Piper betle L extract and Manuka honey, oxoferin, and base both have activity in accelerating acute wound healing.