In this study, molecular interactions of prostate-specific membrane antigen (PSMA) with five chemically distinct urea-based boron-containing inhibitors have been investigated at the atomic level using molecular docking and molecular dynamics simulations. The PSMA–inhibitor complexations have been analyzed by comparing their binding modes, secondary structures, root-mean-square deviations, noncovalent interactions, principal components, and binding free energies. PSMA is a cell surface glycoprotein upregulated in cancerous cells and can be targeted by boron-labeled inhibitors for boron neutron capture therapy (BNCT). The effective BNCT requires the selective boron delivery to the tumor area and highly specific PSMA-mediated cellular uptake by tumor. Thus, a potent inhibitor must exhibit both high binding affinity and high boron density. The computational results suggest that the chemical nature of inhibitors affects the binding mode and their association with PSMA is primarily dominated by hydrogen bonding, salt bridge, electrostatic, and π–π interactions. The binding free energies (−28.0, −15.2, −43.9, −23.2, and −38.2 kcal/mol) calculated using λ-dynamics for all inhibitors ( In1–5 ) predict preferential binding that is in accordance with experimental data. Among all inhibitors, In5 was found to be the best candidate for BNCT. The binding of this inhibitor to PSMA preserved its overall secondary structure. These results provide computational insights into the coordination flexibility of PSMA and its interaction with various inhibitors. They can be used for the design and synthesis of efficient BNCT agents with improved drug selectivity and high boron percentage.