Among the human E3 ubiquitin ligases, NEDD4 (Neural precursor cell expressed developmentally down-regulated 4) plays a critical role in development and cancer, making it a compelling therapeutic target. However, no specific NEDD4 inhibitors have advanced in drug development. In this study, we reveal the inhibitory mechanism of Norclomipramine, a tricyclic antidepressant, which inhibits NEDD4-mediated ubiquitin chain elongation by binding to a hydrophobic pocket in the Ub exosite of the N-lobe. Building on this mechanism, we conducted a focused medicinal chemistry campaign, resulting in the development of covalent inhibitors that specifically target the non-catalytic cysteine C627. These compounds exhibit selective binding to NEDD4 over other family members, effectively inhibiting NEDD4-mediated polyubiquitination while leaving monoubiquitinated substrates unaffected. Among these, compound 32 emerged as a potent lead (IC₅₀ = 0.12 µM) with favorable pharmacokinetic properties, including oral bioavailability, paving the way for future in vivo efficacy studies. (Figure presented.)