Background: Arthritis pain is primarily managed by nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac. Topical diclofenac gel is limited in efficacy due to its limited penetration through the skin. This study investigates the use of a multihour, wearable, localized, sonophoresis transdermal drug delivery device for the penetration enhancement of diclofenac through the skin. Materials & methods: A commercially available, sustained acoustic medicine (sam®) ultrasound device providing 4 h, 1.3 W, 132 mW/cm2, 3 MHz ultrasound treatment was evaluated for increasing the drug delivery of diclofenac gel through a human skin model and was compared with standard of care topical control diclofenac gel. Results: Sonophoresis of the diclofenac gel for 4 h increases diclofenac delivery by 3.8× (p < 0.01), and penetration by 32% (p < 0.01). Conclusion: Sustained acoustic medicine can be used as a transdermal drug-delivery device for nonsteroidal anti-inflammatory drugs.