Digital dermatitis (DD) is a major cause of lameness in dairy cows, resulting in pain and leading to reduced animal welfare and significant economic loss. Strict antibiotic regulations in organic dairy systems create the need for validation of non-antibiotic treatment options. Our objective was to evaluate the efficacy of the treatment of DD using different combinations of copper sulfate, honey, and iodine. Cows at early stages of DD (M1 = early stage, skin defect < 2 cm diameter; and M2 = acute active ulcerative lesion) were identified and enrolled. Study cows (n = 70) were randomly assigned to 1 of 3 topical treatment options: (1) Copper sulfate and iodine (CS-I); (2) honey and iodine (HO-I); and (3) nontreated controls (CON). A clean paper towel was impregnated with the corresponding formulation (10 mL) and applied topically to the lesion with a bandage and maintained for 3 d. Cows were subject to follow-up on d 3, d 12, and d 28 post-treatment to evaluate lesion stage and size, pain response, and lameness score. A subsample of 45 cows were monitored at d 120. All cows continued going through copper sulfate footbaths after milkings. Data were subject to repeated measures analysis for continuous and categorical data. Early erosive lesions (M1/M2) progressed into papillomatous mature forms (M4), irrespective of the treatment group. On d 3 and d 12, lesion size differed and was smaller for HO-I group (P < 0.001). Treatment effect changed in subsequent evaluations (d120), with smaller lesions for CS-I and CON groups vs. HO-I (P < 0.001). The interaction between time and treatment was significant for pain reaction (P < 0.001). The odds (95% CI) of pain for cows in the CON group at d 3 and at d 12 were 7.69 (1.70–3.33) and 4.00 (1.01–16.7) times the odds of pain for animals in CS-I group, respectively. However, at d 120 the odds of pain for cows in the HO-I group were 15.2 (1.60–147) times the odds of pain for animals in CON group. The odds of lameness score > 1 decreased until d 28 and again increased on d 120 (P < 0.001) for all the treatment groups, with the highest incidence in HO-I group. Non-antibiotic treatment options were effective in controlling DD early after treatment. The CS-I combination was superior to both treatment with HO-I and no-treatment in CON group.