Two-dimensional (2D) nanochannel membranes with precise ion sieving properties have emerged as promising materials for direct lithium extraction from salt lake brines. However, the ion selectivity of 2D nanochannel membranes is severely restrained due to water-induced swelling when operating in complex brine conditions. Here, we propose a cation–organic interlayer interlocking strategy to construct an anti-swelling 2D nanochannel membrane with robust channel structure and excellent Mg²⁺/Li⁺ separation performance. The coordinative interlocking between diethylenetriaminepentaacetic acid (DTPA) and Fe³⁺ imposed strong electrostatic confinement between nanosheets, enabling a stable nanochannel structure even in brine with high Mg²⁺/Li⁺ ratio. The presence of DTPA induces a localized concentration gradient of water in the nanochannel, facilitating the formation of Mg²⁺ clusters. These clusters can enhance the steric hindrance of Mg²⁺ and the charge repulsion between Mg²⁺ and Fe³⁺, thereby producing a high Mg²⁺ transport energy barrier. Consequently, the assembled membranes exhibit a Mg²⁺ rejection of 100% in various Mg²⁺/Li⁺ ratio brine environments. This strategy provides insights into tailoring the nanochannel environment to achieve enhanced stability and ion selectivity simultaneously, providing guidance for the development of 2D nanochannel membranes in resource recovery and energy conversion fields.