As a trypanosomatid, L. major begins its lifecycle in amastigote form in the midgut of the main vector, female sand flies (Phlebotomus spp.).

[6] Once in the gut of the sand fly, the parasites change from aflagelated amastigotes into flagellated promastigotes for 1–2 weeks until they are fully developed, a which point they make their way to the proboscis.

[5] Being equipped to survive the acidic environment inside the phagosomes of macrophages, the amastigotes reproduce through the process of binary fission.

[5] These nodules then ulcerate, although due to the variable characteristics of the lesions, species specific identification of the pathogen is impossible.

[5] Generally though, lesions appear moist and have raised outer borders, a granulating base, an overlying layer of white purulent exudate, and have been described as "pizza-like.

"[4][5] Biopsies of these lesions usually reveal a number of findings including numerous macrophages containing intracellular amastigotes as well as lymphocytes with observed granuloma formation and few parasites.

[22] Leishmania major should be considered in the differential diagnosis of chronic lesions of people who have spent time in areas where it is endemic.

However, other pathogens can cause similar lesions and therefore paracoccidiodomycosis, histoplasmosis, sporotrichosis, lobomycosis, lupus vulgaris, Mycobacterium ulcerans, syphilis, cutaneous sarcoidosis, and leprosy should all be considered as well.

[5] The most common ways of diagnosing leishmaniasis are to identify amastigotes in a Wright-Giemsa-stained touch preparation or through isolation of the parasites in cultures.

[5] Because the host's immune system tends to resolve infection after 3–6 months, treatment of the lesions generally focuses on limiting tissue damage and necrosis.

The spread of leishmaniasis can be prevented by interrupting the sand fly life cycle or removing or treating pathogen reservoirs.