The chemical properties of disulfides are leveraged in a wide array of applications, ranging from protein-drug conjugates for cancer treatment to self-healing materials. However, disulfide reduction strategies remain severely underdeveloped despite being the key to efficiently accessing the desired targets. Specifically, no homogeneous catalyst has been reported for this reaction, and conditions that allow the use of mild and green reductants (e.g., via electrochemical reduction) are not known. Herein, we unveil a vitamin B12-catalyzed, electrochemically driven protocol for efficiently reducing disulfide bonds in various aqueous buffers over a broad pH range. This robust and simple method is suitable for disulfide reductions of substrates ranging from small molecules to large proteins. Finally, one-pot reduction and conjugation of disulfide bonds in a monoclonal antibody were demonstrated to produce antibody conjugates.