Lichen is a unique symbiotic organism that consists of fungi and photosynthetic algae and or cyanobacteria. They are known for producing a large repository of secondary metabolites, among which depsides and depsidones gain pharmacological interest. This review meticulously examines the anticancer efficacy of lichen-derived depsides and depsidones, with a focus on their chemical composition, biosynthetic pathways, and molecular mechanisms that underpin their antitumor activities across various cancer cell lines. These compounds have shown notable bioactivities, including cytotoxicity, apoptosis, and suppression of critical oncogenic cascades such as cellular proliferation, metastasis, and angiogenesis. In some studies, they have shown their selectivity for malignant cells while having minimal cytotoxicity towards healthy cells. This review also addresses the challenges for isolation and large-scale production of these metabolites and also explores the aspect of chemical synthesis or designing of synthetic analogues to increase stability, potency, and pharmacokinetic profile. In conclusion, this review emphasizes the potential application of depsides and depsidones as natural anticancer drugs, as studies strongly recommend conducting further analysis using laboratory models. Keywords: anticancer | biosynthesis pathway | depsides | depsidones | lichen metabolites.