The formation of the pyroglutamate variant of amyloid beta (pGlu-Aβ), which is extremely hydrophobic, rapidly aggregating, and highly neurotoxic, is mediated by the action of secretory glutaminyl cyclase (sQC). The pGlu-Aβ often acts as a seed for the aggregation of the full length Aβ and contributes to the overall load of Aβ plaques in Alzheimer's disease (AD). Therefore, inhibiting sQC is a potential approach to limit the formation of pGlu-Aβ and to modify the progression of AD. This study presents two novel molecules containing benzimidazole-6-carboxamide, namely LSB-09 and LSB-24, as promising sQC inhibitors. These inhibitors demonstrated moderate toxicity in human neuroblastoma cell lines and possessed IC50 values in the micromolar range (40 and 4 μM for LSB-09 and LSB-24, respectively). Additionally, the X-ray crystal structure of the sQC-LSB-09 complex revealed a unique binding mode, and a systematic computational investigation elucidated the binding mode for LSB-24. The binding mode of these two benzimidazole-6-carboxamide inhibitors offers a potential platform for designing attractive lead candidates against sQC.