<p>In this paper, we investigate the blow-up dynamics of nonlinear reaction–diffusion equations with space-time dependent coefficients under nonlocal boundary flux, where the domain is divided into subregions by a smooth interface, with nonhomogeneous boundary conditions imposed on distinct segments of the partitioned boundary. Initially, auxiliary functions are constructed to estimate upper bounds for the blow-up time across diverse parameter regimes. Subsequently, a novel auxiliary function is employed, incorporating Sobolev’s inequality, Young’s inequality, and modified differential inequalities under the specified assumptions, to establish lower bounds for the blow-up time. The theoretical results are validated through two specific examples, demonstrating the effectiveness of the proposed method. Additionally, numerical simulations are utilized to intuitively demonstrate the rapid increase in the solution under minor temporal perturbations, thereby reinforcing the conclusions of the theoretical analysis.</p>