In this study, calcined Mg-Al layered double hydroxide (Mg-Al-CLDH) was successfully synthesized for boron (B) removal from aqueous solutions. Batch experiments were conducted considering various reaction conditions, including initial pH, reaction temperature, initial B concentration, Mg-Al-CLDH dosage, ambient condition, and co-existing ions effect, for optimizing B removal efficiency. Results showed that sorption kinetic rate became higher by approaching towards the neutral pH conditions, while it declined at the strong acidic or alkaline conditions. Mg-Al-CLDH was capable of removing high B concentration (80 mg/L) from aqueous solutions at a reasonable dosage of 2 g/L, with a comparable sorption capacity (22.1 mg/g) to other reported studies. Moreover, high B removal rates were observed at high reaction temperatures, reflecting the endothermic nature of the reaction, and reached equilibrium within less than 6 h at temperature of 70 °C. Moreover, results of 3D-RSM modeling confirmed that the middle-high range of Mg-Al-CLDH dosage values was the suitable range to achieve high B removal efficiency, in spite of pH, temperature, and initial concentration effects. Furthermore, isotherm modeling confirmed that B removal by Mg-Al-CLDH occurred via a mono-layer sorption, and thermodynamic modeling revealed the positive value of entropy change, indicating that the randomness of the solid/liquid interaction increased within the adsorption process of B. Spent Mg-Al-CLDH showed great reusability performance by achieving 67%–75% B removal efficiency over three consecutive regeneration cycles, confirming the high potential and applicability of the presented adsorbent in real water treatment applications.