Objectives: This review article highlights a remarkable class of compounds (polyketides) and their derivatives produced by fungi of genus Penicillium and the diversity of their biological activities, isolated, identified and biologically assessed. The species belong to this genus represent a large part of microbial diversity and one of the promising resources in the search of biologically active natural scaffolds. Penicillium genera are one of the most important sources of different secondary metabolites of a wide range of classes of chemical compounds, i.e., anthraquinones, benzodiazepines, coumarins, diketopiperazines, ergot alkaloids, polyketides, quinolines, quinazolines, steroids and terpenoids. Interest in these metabolites increases owing to their valuable pharmacological and therapeutic properties. Methods: This review includes articles between 1988 and 2018, reviewed by internationally accepted databases and scientific journals. Results: This review demonstrates the structural and biological diversity of fifty-three polyketides isolated from different Penicillium species highlighting the culture media used for fungal growth and solvent of extraction along with biological activities and the reported biological assays used to estimate the potential activities of the reviewed polyketides. Conclusion: The structural and biological diversity and potency of reviewed Penicillium polyketides along with the reproducibility of their production make them a perfect candidate for the discovery of new potent pharmaceuticals.