Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+) dependent enzymes, which undergo robust deacetylase activity, resulting in the production of nicotinamide. It is well known that nicotinamide which is one of the products, can also acts as an inhibitor for further deacetylation process by forming the NAD+ again. Hence, the removal of nicotinamide from sirtuins is a demanding process, and the mechanistic understanding of the process remains elusive. In this investigation, we have made an attempt to unravel the unbinding pathways of nicotinamide from SIRT1, SIRT2 and SIRT3 (SIRT1-3) using Random Acceleration Molecular Dynamics (RAMD) Simulations and we have successfully identified various unbinding channels. The selectivity of the egression channel is determined by using a thorough analysis of the frequency of egression trajectories. Similarly, various inhibitors have been docked with the active sites of SIRT1-3 and their egression pathways have been investigated to understand whether they follow the same egression pathway as that of nicotinamide. The residues that are responsible for the unbinding pathways have been determined from the analysis of RAMD trajectories. From these results, it is clear that phenylalanine and histidine residues play major role in the egression of inhibitors. Additionally, the key residues Leu, Pro, Met, Phe, Tyr, and Ile are found to control the release by acting as gateway residues. The role of these residues from different egression channels has been studied by carrying out mutation with alanine residue. This is the first report on sirtuins, which demonstrates the novel unbinding pathways for nicotinamide/inhibitors. This work provides new insights for developing more promising SIRT1-3 inhibitors.