K-Ras is the most commonly mutated oncogene in human cancer, yet direct small-molecule targeting of K-Ras mutants has been mostly unsuccessful until recently. The discovery of an allosteric pocket under Switch-II with covalent cysteine-crosslinking molecules has allowed for the development of targeted therapies that selectively engage the highly reactive acquired cysteine in the K-Ras(G12C) mutation without affecting the wild-type protein. Sotorasib and adagrasib, two advanced Switch-II Pocket inhibitors, have received FDA approval to treat K-Ras(G12C)-driven non-small cell lung cancer. However, the most frequent K-Ras mutation G12D particularly prevalent in pancreatic ductal adenocarcinoma has remained untargetable with covalent drugs due to the poor nucleophilicity of the somatic aspartate residue. Here we present a set of β-lactone-based electrophiles which exploit ring strain to crosslink K-Ras(G12D) at the mutant aspartate to form stable covalent complexes in cells, effectively blocking Ras-effector interaction and downstream signaling. Structural insights from x-ray crystallography and exploitation of the differential chemoselectivity and stereoelectronic requirements for attack of the β-lactone electrophile allowed development of a substituted β-lactone which resisted attack by aqueous buffer but enabled rapid attack by aspartic acid-12 in K-Ras. Our results demonstrate the rational design of covalent inhibitors to target a non-catalytic carboxylic acid side chain in K-Ras(G12D) which has resisted traditional drug discovery efforts.