Background: The aim of this study was to assess the associated-risk determinants for cutaneous leishmaniasis (CL) in patients with diabetes mellitus (DM) compared to patients without diabetes. Methods: This work was performed as a case-control study between 2016 and 2019 in southeastern Iran. Participants were selected from patients with DM without CL, patients with CL without DM, and DM patients co-infected with CL as case groups and healthy individuals as a control group. The groups were screened, interviewed, and clinically examined. These cases were compared for parasitological, immunological, biochemical, and hematological parameters. T-test, univariate, multivariate logistic regression, univariate and multivariate multinomial logistic regression analyses were performed to compare the inter- and intra-subgroups. P < 0.05 was defined significant. Results: The findings demonstrated that parasitological factors regarding the number, duration, and size of the lesion in CL patients showed a significant difference among patients with and without diabetes (p < 0.05). Data analysis showed that six major risk factors, including female (odds ratio (OR) = 3.47, confidence interval (CI) =1.84–6.53, p < 0.001), total protein in CL group (OR= 4.9, CI=2.3-10.44, p <0.001), alanine aminotransferase (ALT) concentration in CL group (OR= 0.87, CI=0.81-0.93, p<0.001) and DM co-infected with CL group (OR= 0.8, CI=0.72-0.88, p <0.001) than healthy group, aspartate aminotransferase (AST) concentration in DM group (OR= 0.86, CI=0.76-0.98, p =0.02), transforming growth factor beta )TGF-β( level in the CL group (OR= 1.03, CI=1.003-1.05, p=0.02) and presence of diabetes disease (OR = 2.07, CI = 1.16–3.7, p < 0.05) were significantly linked with the induction of CL lesion. Furthermore, the parasitological, immunological, biochemical, and hematological findings were different from the CL group to DM co-infected with CL group.Conclusions: The findings demonstrated that there was a significant relationship between DM and CL in distinct risk determinants. Also, the study revealed that DM enhanced the severity of active CL. Therefore, proper prophylactic and therapeutic measures should be taken in endemic countries where DM and CL are co-infected.