We aimed to assess safety and dose-finding efficacy of esmolol hydrochloride (Galnobax) for healing of diabetic foot ulcer (DFU). This is phase 1/2 multicenter, randomized, double-blind vehicle-controlled study. Participants having diabetes and noninfected, full-thickness, neuropathic, grade I or II (Wagner classification) DFU, area 1.5-10 cm2, and unresponsive to standard wound care (at least 4 weeks) were randomized to receive topical Galnobax 14% twice daily (BID), Galnobax 20% BID, Galnobax 20% once daily (OD)+vehicle, or vehicle BID with standard of care. The primary efficacy end point was the reduction in area and volume of target ulcer from baseline to week 12 or wound closure, whichever was earlier. The wound duration was 12.5 weeks (5-49.1 weeks) and wound area 4.10 ± 2.41 cm2 at baseline. The ulcer area reduction was 86.56%, 95.80%, 80.67%, and 82.58% (p = 0.47) in the Galnobax 14%, Galnobax 20%, Galnobax20%+vehicle, and vehicle only groups, respectively. Ulcer volume reduction was 99.40% in the Galnobax14%, 83.36% in Galnobax20%, 55.41% in the Galnobax20%+vehicle, and 84.57% in vehicle group (p = 0.86). The systemic concentration of esmolol was below the quantification limit (10 ng/mL) irrespective of doses of Galnobax (Cmax esmolol acid 340 ng/mL for 14% Galnobax, AUC 2.99 ± 4.31 h*μg/mL after single dose). This is the first clinical study of the short acting beta blocker esmolol hydrochloride used as novel formulation for healing of DFU. We found that esmolol when applied topically over wounds had minimal systemic concentration establishing its safety for wound healing in patients with diabetes. Esmolol hydrochloride is a safe novel treatment for DFU.