Clathrin-mediated endocytosis (CME) is the predominant endocytic pathway in eukaryotic cells and a major regulator of cell physiology as it facilitates the internalization of receptors, channels, and transporters and viral entry. The clathrin terminal domain acts as a central protein interaction hub within the endocytic protein network. Previously described inhibitors of CME display off-target activities that result in cytotoxicity, providing limitations to their use. We report the development and characterization of next-generation small molecule inhibitors of clathrin terminal domain function. These compounds termed Pitstop 2c and Pitstop 2d occupy the binding site within the clathrin terminal domain for endocytic protein ligands including epsin, resulting in potent inhibition of receptor-mediated endocytosis and reduced entry of vesicular stomatitis virus (VSV) with minimal cytotoxic side effects. Next-generation Pitstops thus provide an improved toolset to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry.