Considering the role of the nucleus accumbens (NAcc) as a common neurobiological substrate for the interplay between these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male and female mice modeled to schizophrenia with a history of adolescent nicotine exposure. Phencyclidine was used to model schizophrenia and minipump infusions was used to model nicotine misuse. Enrichment Reactome pathway and protein–protein interaction analyses revealed the cytoskeleton and associated synaptic plasticity mechanisms, energy metabolism, and nervous system development, as affected in both females and males modeled to the comorbid condition.