Exosome-like particles (ELPs) derived from natural products have attracted considerable interest for drug delivery and therapeutic applications. Mushroom-derived exosome-like particles (MELPs) are an unexplored group with significant biomedical potential. Because medicinal and edible mushrooms are rich in bioactive compounds, such as polysaccharides, proteins, and phenolic acids, it is likely that their ELPs also carry these compounds during their biogenesis. Hence, MELPs containing these beneficial compounds, which exhibit favorable characteristics such as nanosize, stability, and cellular uptake properties, should be considered a novel potential natural nanocarrier. Here, we have detailed the current understanding of MELPs in terms of their biological functions, physicochemical characteristics, molecular cargo, and isolation methods. We have also highlighted their potential applications in cancer therapy, immune modulation, inflammation, and microbiome regulation. Moreover, we have outlined the challenges and future directions for standardizing the isolation protocol to yield large-scale production and for elucidating the mechanistic pathways. As MELP research advances, it may emerge as a next-generation nanocarrier in natural therapeutics and green nanomedicine.