Objective <p>To evaluate the clinical efficacy and safety of Zizhu Ointment (ZZO) in treating Wagner grade 2 diabetic foot ulcers (DFUs).</p> Methods <p>In this single-center, randomized, double-blind, placebo-controlled trial, using SPSS 26.0, a computer-generated random number sequence was used to randomly assign 154 patients with Wagner grade 2 DFUs in a 1:1 ratio to either the ZZO group (<i>n</i>=77) or the placebo control group (<i>n</i>=77). Both groups received conventional therapy and standard debridement. Patients received the assigned intervention as a topical application for 6 weeks, followed by a 6-week follow-up period. The primary outcome was the ulcer healing rate at 6 weeks. Secondary outcomes included Chinese medicine (CM) syndrome scores, transcutaneous oxygen pressure (TcPO₂), wound blood flow, and safety indicators.</p> Results <p>After 6 weeks, the ulcer healing rate was significantly higher in the ZZO group than in the placebo control group (67.59% ± 22.69% vs. 28.81% ± 15.80%, <i>P</i>&lt;0.001). This superiority was maintained at the end of the 6-week follow-up (80.95% ±19.16% vs. 42.20% ±21.93%, <i>P</i>&lt;0.001). The ZZO group also demonstrated significantly greater improvements in reducing ulcer area and depth, improving CM syndrome scores, TcPO₂, and wound blood flow (all <i>P</i>&lt;0.05). The incidence of adverse events was comparable between the two groups (<i>P</i>&gt;0.05).</p> Conclusions <p>ZZO effectively promotes the healing of Wagner grade 2 DFUs, ameliorates the wound microenvironment and CM symptoms, and exhibits a favorable safety profile. (Registration No. ITMCTR2025000126)</p>