Autophagy is a contentious issue in leishmaniasis and is emerging as a promising therapeutic regimen. Published research on the impact of autophagic regulation on survival is inconclusive, despite numerous pieces of evidence that spp. triggers autophagy in a variety of cell types. The mechanistic approach is poorly understood in the parasite as autophagy is significant in both and the host. Herein, this review discusses the autophagy proteins that are being investigated as potential therapeutic targets, the connection between autophagy and lipid metabolism, and microRNAs that regulate autophagy and lipid metabolism. It also highlights the use of systems biology to develop novel autophagy-dependent therapeutics for leishmaniasis by utilizing artificial intelligence (AI), machine learning (ML), mathematical modeling, network analysis, and other computational methods. Additionally, we have shown many databases for autophagy and metabolism in parasites that suggest potential therapeutic targets for intricate signaling in the autophagy system. In a nutshell, the detailed understanding of the dynamics of autophagy in conjunction with lipids and miRNAs unfolds larger dimensions for future research.