Blue nail discoloration is a distinctive clinical presentation, and diagnosis is challenging given the broad differential diagnosis. A comprehensive review of the literature describing blue discoloration of one or multiple nails was performed using the PubMed, Embase, Scopus, and Web of Science databases. A total of 245 publications were included and grouped based on involvement of a single nail (monodactylic) or multiple nails (polydactylic). Monodactylic blue discoloration was associated with tumors or benign nevi, most commonly glomus tumors, followed by blue nevi and less commonly melanomas. Polydactylic blue discoloration was frequently associated with medications (such as minocycline, zidovudine, and hydroxyurea), toxic and exogenous exposures (such as silver), and other medical conditions (such as HIV/AIDS and systemic lupus erythematous). Patients presenting with blue nail discoloration warrant a thorough history, physical examination, and workup to rule out malignancy, systemic disease, or toxic exposure. We present diagnostic algorithms for monodactylic and polydactylic blue nail discoloration to guide workup and treatment plans.