Trophoblast cell surface antigen 2 (Trop2) is a transmembrane glycoprotein overexpressed in many epithelial cancers and functions as a critical driver of tumor growth, metastasis, and therapeutic resistance. While Trop2-targeting antibody–drug conjugates (ADCs) such as sacituzumab govitecan have demonstrated clinical success, limitations including off-target toxicity and drug resistance underscore the need for alternative modalities. This review explores recent advances in the development of small molecule inhibitors targeting Trop2, with a focus on structure-based strategies. We summarize the oncogenic signaling mechanisms of Trop2, including regulated intramembrane proteolysis and β-catenin stabilization, and identify key structural domains such as the TY-loop, ND–CD ridge, and intracellular phosphorylation region (Ser303, Lys307, Glu310) as candidate binding pockets. Bruceine D is presented as a case study of a natural Trop2-ICD modulator, supported by docking analyses and structure activity insights. In addition, we examine fragment-based drug discovery, covalent/allosteric inhibition, and AI-guided screening strategies, integrating computational and experimental workflows including CETSA, luciferase assays, and ADMET filtering. Together, these approaches provide a comprehensive framework for the rational design and optimization of next-generation Trop2-targeted small molecule therapeutics.