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The history of tri-substituted methanes (TRSMs) in chemical industries is much older. Tri-substituted methanes were previously used as dyes in the chemical industries. Still, there is a significant surge in researchers' interest in them due to their wide range of bioactivities. Tri-substituted methane derivatives show a wide range of biological activities like anti-tumor, antimicrobial, antibiofilm, antioxidant, anti-inflammatory, anti-arthritic activities. Due to the wide range of medicinal applications shown by tri-substituted methanes, most of the methodologies reported in the literature for the synthesis of TRSMs are focused on the one-pot method. This review explored the recently reported one-pot processes for synthesizing tri-substituted methanes and their various medicinal applications. Based on the substitution attached to the -CH carbon, this review categorizes them into two major classes: (I) symmetrical and (II) unsymmetrical trisubstituted methanes. In addition, this review gives an insight into the growing opportunities for the construction of trisubstituted scaffolds via one-pot methodologies. To the best of our knowledge, no one has yet reported a review on the one-pot synthesis of TRSMs. Therefore, here we present a brief literature review of the synthesis of both symmetrical and unsymmetrical TRSMs covering various one-pot methodologies along with their medicinal applications.