Requirements for novel bioconjugation reactions for the synthesis of Antibody‐Drug‐Conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. Herein we describe Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies, applying a simple one‐pot reduction and alkylation protocol. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next generation antibody therapeutics in terms of serum stability and in vivo antitumor activity.