Mycobacterium tuberculosis Nei2 (Rv3297) is a BER glycosylase that removes oxidized base lesions from ssDNA and replication fork-mimicking substrates. We show that Endonuclease VIII 2 (Nei2) forms a BER complex with the β-clamp (DnaN, Rv0002) with a KD of 170 nM. The Nei2-β-clamp interactions enhance Nei2’s activities up to several folds. SEC analysis shows that one molecule of Nei2 binds to a single β-clamp dimer. Nei2 interacts with subsites I and II of the β-clamp via a non-canonical 223QGCRRCGTLIAY239 Clamp Interacting Protein (CIP) motif in the C-terminal zinc-finger domain, that was previously shown by us to be dispensable for intrinsic Nei2 activity. The 12-mer peptide alone exhibited a KD of 10.28 nM, suggesting that the motif is a key mediator of Nei2-β-clamp interactions. Finally, we identified inhibitors of Nei2-β-clamp interactions using rational methods, in vitro disruption, and SPR assays after querying a database of natural products. We found that Tubulosine, Fumitremorgin C, Toyocamycin, and Aleuritic acid exhibit IC50 values of 94.47 µM, 83.49 µM, 109.7 µM, and 71.49 µM, respectively. They act by disrupting Nei2-β-clamp interactions and do not affect intrinsic Nei2 activity. Among other things, the present study gives insights into the role of Nei2 in bacterial pre-replicative BER.