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Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a dodecameric serine/threonine kinase highly enriched at synapses and essential for synaptic plasticity. However, why CaMKII is present in such high abundance—often exceeding the levels of its substrates—remains unclear. Here, we show that CaMKII activation by Ca²⁺/calmodulin induces liquid–liquid phase separation (LLPS) with substrate proteins, leading to the formation of biomolecular condensates that concentrate synaptic proteins. Once initiated, these condensates persist even after Ca²⁺ levels decline, indicating that CaMKII contributes not only through its kinase activity but also by organizing synaptic nanodomains. When AMPA-type and NMDA-type glutamate receptors (AMPARs and NMDARs) were incorporated into these condensates, they formed distinct synaptic nanodomains within a shared phase-separated compartment, suggesting that LLPS provides a mechanism for subtype-specific receptor segregation. Disruption of the CaMKII–NMDAR interaction in vivo reduced this segregation, further supporting a role for CaMKII in regulating synaptic nanodomain architecture through biomolecular condensation.