This study introduces a novel acrylamide Schiff base hydrogel, specifically designed for efficient uranium removal from polluted environments. We thoroughly characterized the hydrogel using various techniques and then systematically evaluated its adsorption performance through batch experiments. These experiments explored the impact of pH, contact time, initial ion concentration, adsorbent dosage, and temperature. Under optimal conditions—pH 4.0, 120 minutes contact time, 70 mg adsorbent, 298 K, and 100 mg L⁻¹ uranium(VI) concentration—the hydrogel achieved an impressive 99.92% removal efficiency for uranyl ions. Notably, a lower adsorbent dose of just 5 mg yielded a high maximum adsorption capacity of 148 mg g⁻¹. Our analysis of adsorption isotherms and kinetics showed that the data fit best with the Langmuir model (R² = 0.98) and pseudo-second-order kinetics (R² = 0.99), suggesting a monolayer chemisorption mechanism. The Langmuir model also predicted a maximum adsorption capacity of 159.23 mg g⁻¹. Thermodynamic studies confirmed that the adsorption was a spontaneous and exothermic process. The hydrogel also exhibited excellent selectivity and strong resistance to interference from other ions present in the water. We used Central Composite Design (CCD) and Response Surface Methodology (RSM) to optimize key operational parameters and develop a predictive polynomial model. Finally, we successfully applied the hydrogel to remediate a real water sample, demonstrating its practical viability.