Humans are constantly exposed to exogenous chemicals throughout their life, which can lead to a multitude of negative health impacts. Advanced materials can play a key role in preventing or mitigating these impacts through a wide variety of applications. The tunable properties of hydrogels and hydrogel nanocomposites (e.g., swelling behavior, biocompatibility, stimuli responsiveness, functionality, etc.) have deemed them ideal platforms for removal of environmental contaminants, detoxification, and reduction of body burden from exogenous chemical exposures for prevention of disease initiation, and advanced treatment of chronic diseases, including cancer, diabetes, and cardiovascular disease. In this review, three main junctures where the use of hydrogel and hydrogel nanocomposite materials can intervene to positively impact human health are highlighted: 1) preventing exposures to environmental contaminants, 2) prophylactic treatments to prevent chronic disease initiation, and 3) treating chronic diseases after they have developed.