The blood–brain barrier (BBB) is a specialized semipermeable structure that regulates the exchange between the central nervous system (CNS) and the bloodstream, preventing the passage of therapeutic agents and nanocarriers. Recent multidisciplinary efforts have focused on developing cargo-loaded nanoparticles (NPs) to overcome these barriers, making them promising vehicles in neurotheranostics. This review introduces the anatomical structure and physiological functions of the BBB, detailing the endogenous and exogenous transport mechanisms by which NPs can cross it. It discusses various nanomaterials, carriers, and their cargos, along with their BBB uptake and permeability characteristics. The effect of size, shape, charge, and surface ligands on NP BBB permeability is explored, highlighting strategies to enhance neurotheranostics. The review also covers recent progress in developing functional polymeric nanomaterials for multimodal bioimaging, therapeutics, and drug delivery. Finally, it discusses existing challenges, directions, and future perspectives in employing functionalized nanomaterials for BBB crossing.The blood–brain barrier (BBB) is a specialized semipermeable structure that regulates the exchange between the central nervous system (CNS) and the bloodstream, preventing the passage of therapeutic agents and nanocarriers. Recent multidisciplinary efforts have focused on developing cargo-loaded nanoparticles (NPs) to overcome these barriers, making them promising vehicles in neurotheranostics. This review introduces the anatomical structure and physiological functions of the BBB, detailing the endogenous and exogenous transport mechanisms by which NPs can cross it. It discusses various nanomaterials, carriers, and their cargos, along with their BBB uptake and permeability characteristics. The effect of size, shape, charge, and surface ligands on NP BBB permeability is explored, highlighting strategies to enhance neurotheranostics. The review also covers recent progress in developing functional polymeric nanomaterials for multimodal bioimaging, therapeutics, and drug delivery. Finally, it discusses existing challenges, directions, and future perspectives in employing functionalized nanomaterials for BBB crossing.