Abstract: Cellular uptake of nanomaterials is a critical prerequisite for biomedical functions such as antitumor drug delivery, nucleic acid transfection, and molecular imaging. Beyond particle size and surface chemistry, shape as an independent design parameter has attracted growing attention for its influence on cellular uptake behavior. This review systematically summarizes the differences in cellular uptake of nanomaterials with typical morphologies—including spheres, rods, sheets/discs, stars, triangles, and membrane wrapping, exhibit relatively high uptake efficiency in many gold nanoparticle and polymer cubes—across various experimental systems. Spherical particles, owing to their isotropic structure and stable systems. The uptake of rod-shaped materials is highly dependent on aspect ratio and contact orientation: moderate aspect ratios facilitate internalization, whereas excessively high ratios may increase the membrane wrapping energy barrier. The advantages of sheet- and disc-shaped particles are manifested more in margination within blood flow, vascular adhesion, and prolonged circulation half-life rather than in absolute cellular uptake levels. Special shapes such as stars and triangles, through their tips and high-curvature regions, influence the protein corona composition, ligand exposure, and receptor binding, thereby altering endocytic behavior. The mechanisms by which shape regulates uptake involve multiple coupled factors, including size and surface curvature, membrane contact and wrapping, endocytic pathways, surface modification, protein corona formation, and cell type. This review further discusses the applied significance of shape engineering in targeted delivery, immune evasion, long circulation, and antitumor therapy, emphasizing that shape design should serve specific delivery scenarios rather than merely pursuing the highest uptake level. Future research should establish predictable shape–function relationships through standardized material platforms, high-resolution imaging, and in vivo validation, thereby advancing shape modulation from fundamental mechanistic understanding toward rational nanocarrier design.