In the present study, the effect of one of the most important lignin-derived inhibitors (lignosulfonate) was assessed. A technique to overcome the lignosulfonate inhibitory action in the acetone−butanol−ethanol (ABE) fermentation process is proposed here. Different lignosulfonates were primarily added in the fermentation medium to observe their mechanistic action on the ABE production profile. Augmenting lignosulfonate concentration (0.5 g L−1) resulted in a drastically reduced solvent titer (ABE ∼1.50 g L−1). Especially, low-molecular-weight linosulfonate (1 g L−1) severely affected the solvent production and completely ceased the fermentation process. Therefore, a strategic approach that triggers the key genes responsible for butanol production was explored. The experimental analysis revealed that soy meal addition could enhance Clostridium acetobutylicum survival in the presence of lignosulfonates (0.25−3 g L−1). Moreover, soy meal addition also enhanced butanol concentration over 1.5-fold as compared to the control experiment. The ABE production using wood hydrolysate also produced substantial solvent titer (ABE ∼11 g L−1) in the presence of soy meal (5 g L−1). The transcriptional analysis results showed that important genes in clostridial metabolic pathways were upregulated in the presence of soy meal addition during fermentation.