Selective GluN2B/N-methyl-D-aspartate receptor (NMDAR) antagonists have exposed their clinical effectiveness in a cluster of neurodegenerative diseases, such as epilepsy, Alzheimer’s disease, Parkinson’s disease, pain, and depression. Hence, GluN2B/NMDARs are considered to be a prospective target for the management of neurodegenerative diseases. Here, we have discussed the current results and significance of subunit selective GluN2B/NMDAR antagonists to pave the way for the establishment of new, safe, and economical drug candidates in the near future. By using summarized data of selective GluN2B/NMDAR antagonists, medicinal chemists are certainly a step closer to the goal of improving the therapeutic and side effect profile of selective antagonists. Outlined summary of designing strategies, synthetic schemes, and pharmacological evaluation studies reinvigorate efforts to identify, modify, and synthesize novel GluN2B/NMDAR antagonists for treating neurodegenerative diseases.