Isocoumarins and dihydroisocoumarins are lactonic phytochemicals plentiful in microbes and higher plants. These are an amazing small scaffolds consecrated with all types of pharmacological applications. Our previous review covered the period 2000–2016, documenting the then known natural products of this class; the current article is a critical account of discovery of known as well as undescribed structural types and pharmacological activities reported in the course of 2016–2020. The classification revealed in our previous review based on the biogenetic origin is further buttressed by discovery of new members of each class and some new structural types hitherto unknown have also been identified. Similarly, the biological activities and SAR conclusions identified were found to be valid as well, nonetheless with new accompaniments. The most recent available literature on the structural diversity and biological activity of these natural products has been included. The information documented in this article are collected from scientific journals, books, electronic search engines and scientific databases. Display omitted •A critical and all-inclusive collection of pharmacological profile of natural isocoumarins.•Identification of new and well known structural types based on biosynthetic origin.•Aims to facilitate synthetic chemists to design selective isocoumarins derivatives.