Background and objective Cutaneous leishmaniasis (CL) is one of the most significant and endemic parasitic infections in many regions around the world, and it is caused by several species of the Leishmania parasite. It is a morbid condition that leads to stigmatization and disfiguring scars. Numerous methods have been tried to treat leishmaniasis with variable cure rates and side effects. This study aimed to compare the effects of oral zinc bisglycinate (ZnGly) and oral hydroxychloroquine sulfate (HCQ), alone and in combination, in treating acute CL. Materials and methods This comparative therapeutic study was conducted at the Center of Dermatology and Venereology, Medical City, Baghdad, Iraq, during the period from December 2021 to February 2023. All participants had been diagnosed through history and clinical examination, which involved skin smear in all patients and skin biopsy for some suspicious cases. Patients were classified into three groups based on the type of treatment: Group A was treated with oral ZnGly capsules 50 mg twice daily for eight weeks; Group B was administered oral HCQ tablets 200 mg twice daily for eight weeks; and Group C received a combination of both drugs for eight weeks. All patients were examined every four weeks for eight weeks, followed by every month for two months after stopping therapy. The treatment's impact on the lesions was assessed using Sharquie`s modified Leishmania score. Results A total of 40 patients with acute CL were included in this study, which spanned eight weeks. The total number of lesions was 144, and their duration ranged from five to 12 weeks. Group A included 14 patients, and the cure rate was 78.6% (11); Group B included 13 patients, and the cure rate was 84.7 % (11), while Group C included 13 patients, and the cure rate was 92.3% (12). We observed a statistically significant difference in the cure rate in Group C when compared to Group A and Group B at the end of the study (p=0.034). Conclusions While both oral ZnGly and HCQ as monotherapy were effective in the treatment of acute CL, the combination regimen of both drugs led to higher effectiveness without any increase in the frequency of adverse effects.