<p>Natural products derived from marine and terrestrial sources have emerged as a significant trend in drug discovery, owing to their remarkable structural diversity and wide-ranging biological activities. These compounds often contain specific pharmacophores responsible for their bioactive properties. The pharmaceutical industry has greatly stimulated the development and application of click chemistry reactions, which facilitate the rapid synthesis of diverse compound libraries for efficient drug screening. While click chemistry encompasses various reaction types, the copper-catalyzed azide-alkyne cycloaddition stands out as the most widely utilized approach. Copper-catalyzed azide-alkyne cycloaddition has been extensively employed to synthesize analogs and hybrids of natural products, enabling researchers to explore and enhance their therapeutic potential. The coupling of distinct molecular entities via click chemistry enables the creation of novel conjugates with combined or improved properties. This article focuses on the application of click chemistry in the modification of natural products, with particular emphasis on the resulting compounds that exhibit new or enhanced biological activities.</p> Graphical Abstract <p></p>