With the rollout of multiple COVID-19 vaccines, adjunctive treatments for COVID-19 have received less attention. Breakthrough infections post-vaccination (including boosters) underscore the need to continue evaluating repurposed drugs and nutraceuticals as candidate adjunctive treatments. Early clinical studies of antihistamines hypothesized that targeting mast cells (and/or histamine receptors) might benefit COVID-19 patients. In cultured human coronary artery endothelial cells, histamine potentiated spike-mediated angiotensin-converting enzyme 2 internalization; this effect can be blocked by the antihistamine famotidine. This literature review focuses on clinical studies of antihistamines, mast cell stabilizers, and leukotriene receptor antagonists for COVID-19 patients. Several antihistamines and mast cell-targeting agents, including fluvoxamine, cyproheptadine, hydroxyzine, and antihistamines used alone or with azithromycin (dexchlorpheniramine, cetirizine, loratadine, and ebastine), as well as azelastine, famotidine (standard or high-dose), high-dose famotidine with celecoxib, and the flavonoid mast cell stabilizer quercetin, have been reported to be associated with clinical benefits in COVID-19 patients. Multiple studies have reported mixed results for aspirin, montelukast, and normal-dose famotidine; patients taking aspirin often have associated COVID-19 risk factors. In the context of current standard-of-care treatments, clinical studies evaluating candidate adjunctive treatments should carefully consider and avoid known drug–drug interactions, such as those involving celecoxib and dexamethasone. Further clinical studies of the identified treatments targeting mast cells and/or histamine receptors in COVID-19 patients associated with clinical benefits are therefore strongly recommended.