OBJECTIVE To investigate the potential of low-frequency, low-power ultrasound to enhance the transdermal absorption and efficacy of ketoprofen gel. METHODS Ketoprofen gel was used as a model drug to compare the in vitro transdermal permeation of ultrasound treated group and untreated group. Additionally, a rat model of collagen-induced inflammation provided a basis for evaluating pharmacodynamic differences. Pharmacokinetic studies further elucidated the effects of ultrasound on ketoprofen gel's penetration process. RESULTS Ultrasound treatment enhanced the cumulative transdermal permeation of ketoprofen gel by 3.5-fold over 24 hours compared to untreated. Significant pharmacokinetic improvements in AUC0-t from (4289.02±763.58)ng·h·mL−1 to (11301.10±3386.30)ng·h·mL−1 and a reduction in Tmax from (6.0±1.4)h to (3.0±2.0)h. Ultrasound notably improved the gel's anti-inflammatory effects in the rat model, effectively and rapidly reducing inflammation-induced swelling. CONCLUSION Low-frequency, low-power ultrasound can significantly improve the amount and rate of transdermal absorption of ketoprofen gel and enhance its pharmacological potency, from the aspects of skin permeation tests, pharmacodynamic evaluation, and pharmacokinetic studies, which is an effective penetration enhancer for transdermal administration of ketoprofen gel.