Modern humans' unique cognitive abilities regarding Neanderthals and other primate's lineages are frequently attributed to the differences in brain size development and evolution. However, recent studies have established the critical role of genomic and genetic benchmarking in analyzing the cognitive evolution between modern humans and primates, focused mainly on searching for involved genes in neurogenesis. PSD95 protein (named PSD95p) has a key role in modulating synaptic plasticity, learning, and memory skills. Thus, the present study aimed to determine the possible variations of the PSD95 gene between modern humans, Neanderthals, and other hominid primate species using bioinformatics tools. The results showed 14 polymorphisms compared with the contemporary human PSD95 gene, of which 13 were silent mutations, and only one was a non-silent mutation at the nucleotide position 281. Despite polymorphisms found at the nucleotide sequences, the PSD95p of humans and chimpanzees are 100% identical. Likewise, the gorilla and orangutan PSD95p are 100% identical, although a 103-amino acid deletion characterizes them at the N-terminal end (1-103), suggesting that it behaves like a non-functional protein. Interestingly, the single nucleotide polymorphism (SNP) found at position 281 in the Neanderthal PSD95 gene leads to a change of the E94 to valine V94 in the polyubiquitination domain (PEST) and variation in the three-dimensional structure of PSD95 protein. We prompt that this structural change in the PEST domain could induce a loss of PSD95p function and, therefore, an alteration in synaptic plasticity forms such as long-term potentiation (LTP) and long-term depression (LTD). These findings open a possible hypothesis supporting the idea that humans' cognitive evolution after separating our last common ancestor with Neanderthals lineage could have been accompanied by discrete changes in the PSD95p polyubiquitination domain.