Papular dermatitis is a cutaneous manifestation of canineLeishmania infantuminfection associated with mild disease. Although it is a typical presentation, nowadays, there is still no established treatment. This study evaluated the safety and clinical efficacy of local meglumine antimoniate, locally administered polyhexamethylene biguanide (PHMB) alone or PHMB in combination with a Toll-like receptor 4 agonist (TLR4a) for the treatment of papular dermatitis due toL. infantumand assessed parasitological and immunological markers in this disease. Twenty-eight dogs with papular dermatitis were divided randomly into four different groups; three of them were considered treatment groups: PHMB (n = 5), PHMB + TLR4a (n = 4), and meglumine antimoniate (n = 10)), and the remaining were considered the placebo group (n = 9), which was further subdivided into two sub-groups: diluent (n = 5) and TLR4a (n = 4). Dogs were treated locally every 12 h for four weeks. Compared to placebo, local administration of PHMB (alone or with TLR4a) showed a higher tendency towards resolution of papular dermatitis due toL. infantuminfection at day 15 (χ2= 5.78; df = 2,p= 0.06) and day 30 (χ2= 4.; df = 2,p= 0.12), while local meglumine antimoniate administration demonstrated the fastest clinical resolution after 15 (χ2= 12.58; df = 2,p= 0.002) and 30 days post-treatment (χ2= 9.47; df = 2,p= 0.009). Meglumine antimoniate showed a higher tendency towards resolution at day 30 when compared with PHMB (alone or with TLR4a) (χ2= 4.74; df = 2,p= 0.09). In conclusion, the local administration of meglumine antimoniate appears to be safe and clinically efficient for the treatment of canine papular dermatitis due toL. infantuminfection.