Background: The skin is a crucial barrier between the body and the external environment; however, its natural healing ability may be compromised in deep injuries. This study aimed to explore the topical therapeutic effects of phonophoresis of 4-aminopyridine (4-AP, a potassium (K+) channel blocker) applied to sutured wound tissue using ultrasound (US/phonophoresis). Methods: This study utilized phonophoresis to enhance the transdermal delivery of 4-AP in 49 male Sprague-Dawley rats. An incision was created in the right facial area of each rat and closed with four separate sutures. The animals were randomly assigned to seven groups (n = 7): Control, Sham, US, 4-AP, and three groups receiving different doses of 4-AP (Low (L), Medium (M), and High (H)) + US. 4-AP was administered topically via the transdermal route in a hydrogel with DMSO. Results: The results showed that 4-AP alone was not sufficiently effective, but the 4-AP + US group showed a 17.9-fold increase in EGFR expression and a 26.2-fold increase in VEGFR expression. The increase in MMP9 activity (28-fold) was in line with the immunohistochemical findings and morphological measurements. Overall, the medium dose appeared to offer a better balance between the rate and quality of recovery. Conclusions: This study presents a regenerative treatment strategy with promising therapeutic effects, promoting tissue restoration through the topical effects of phonophoresis on angiogenesis, proliferation, and tissue remodeling in surgically sutured wounds via US-induced cavitation and 4-AP-mediated ion channel modulation.