Endocytosis is a vital cellular process that serves numerous essential functions, such as the internalization of ligand–receptor complexes, intracellular signal transduction, nutrient uptake, maintenance of cell polarity, and neurotransmission. Numerous specialized endocytic mechanisms have been elucidated based on the diverse characteristics of the ligands, cellular environment, endocytic adaptors, kinase proteins, and membrane lipids composition. Recent methodological advancements and therapeutic interest have significantly contributed to the substantial development of our understanding of the mechanism of endocytosis. We comprehensively discuss the emerging concepts of receptor endocytosis implicated in diverse intracellular mechanisms, the regulation of receptor internalization and subsequent receptor sorting, as well as the ubiquitin modification associated with endocytosis signaling. Finally, we shed light on pathophysiological conditions associated with dysregulated endocytic signaling, particularly Coronavirus Disease-2019 (COVID-19) and rare human diseases.