Leishmaniasis causes skin ulcers to complex visceral involvement, and available treatment options for humans are highly toxic and have prolonged application schemes. So far, there are no licensed vaccines for humans, so it is necessary to develop a strategy that can prevent the development of the disease. A cellular immune response of a CD4⁺ Th1 profile is essential to eliminate intracellular Leishmania amastigotes; therefore, the identification of sequences that bind to HLA class II pockets could induce a protective immune response. This study aimed to identify CD4⁺ T epitopes from immunogenic Leishmania proteins. First, three prediction tools were used to compare 15-mer sequences throughout the complete protein sequence against 25 HLA-DR alleles using NH, SMT, CPA, CPB, and CPC proteins. Six peptides were identified as strong HLA-DR binders using the three bioinformatic prediction tools. After alignment, molecular docking analysis, and molecular dynamics, the stability and affinity of the peptide–DR4 complex were confirmed for three sequences. This bioinformatics strategy allowed a sequential screening from 1857 to three promising candidates, namely, SMT_133-148, CPA_39-54, and CPA_301-316, which increases the probability of being natural Leishmania spp. CD4⁺ T cell epitopes in humans.