Natural products are central to the organic synthesis field and attract immense interest due to their biological activity and wide industrial use. However, many suffer from poor aqueous solubility, instability under certain conditions, or bear complex composition, limiting their investigation and derivatization. Metal–organic cages (MOCs) are promising molecular receptors to solubilize in water, preserve, or transform natural products. This contribution features examples of MOCs that encapsulate naturally occurring compounds and synthetic congeners in aqueous media, protecting them from photodegradation or hydrolysis. We highlight cases of cages used as molecular vessels to promote chemical conversion and derivatization of natural substances. This review aims to provide an overview of the possibilities of using MOCs to bring about new properties and reactivity on natural products, offering methodological insights into cage operation for enhancing their activity and the engineering of further aqueous applications involving natural compounds, synthetic derivatives, and biomolecules.