Cutaneous leishmaniasis (CL) displays a spectrum of manifestations clinically and histologically. Then, it becomes a diagnostic challenge and must discern from the other clinical and histological mimics, especially when the Leishman-Donovan bodies are inattentive. In this study, we compared the distinguishing histomorphological characteristics of CL against the other skin diseases with similar clinical and histological features. Skin biopsies of 181 patients, which suspect CL clinically, are evaluated histologically. Pertaining to the first case–control comparison, which performed between skin lesions of CL with or without discernible organisms and the other granulomatous dermatitis, highlighted that the ill-formed coalescent granulomata (OR = 14.83) and diffuse dense dermal plasma cell infiltrate (OR = 74.25) are significantly associated with the skin lesions of CL. The second case–control analysis was between CL without discernible organisms and the other granulomatous dermatitis, and identified a significant association in the presence of ill-formed coalescent granulomata (OR = 16.94) and diffuse dense (>50/HPF) dermal plasma cell infiltrate (OR = 74.5) in the skin lesions of CL. Pertaining to epidermal changes, acanthosis (OR = 2.38), spongiosis (OR = 9.13), and the presence of ulceration (OR = 20.26) are among the major concerns in CL. In conclusion, in the presence of clinical suspicion, dermal granulomata in ill-formed coalescent morphology with high plasma cell density in a diffuse arrangement are positive factors for the diagnosis of CL, especially when the discernible Leishmania amastigotes are absent. Resource utilization such as polymerase chain reaction and other ancillary techniques during the diagnosis of CL can be minimized by using a range of histopathological features and special attention should be focused on this in the future.