Nickel contamination in water is a critical issue due to its toxicity and persistence. This study presents a novel magnetic resin, developed by modifying Lewatit^® MonoPlus TP 207 with magnetite nanoparticles, to enhance adsorption capacity and facilitate efficient separation. A Definitive Screening Design (DSD) was employed to identify and optimize key parameters affecting nickel adsorption, including pH, resin dosage, initial nickel concentration, and the presence of competing ions (calcium and magnesium). The DSD analysis revealed that pH and magnesium concentration were the most significant factors influencing nickel removal. Optimal conditions were determined as pH 7, 270 min contact time, resin dosage of 0.5 mL/L, initial nickel concentration of 110 µg/L, calcium concentration of 275 mg/L, and magnesium concentration of 52.5 mg/L, achieving a maximum removal efficiency of 99.21%. The magnetic resin exhibited enhanced adsorption capacity and faster kinetics compared to the unmodified resin, leading to more efficient nickel removal. Moreover, its magnetic properties facilitated rapid separation from treated water, offering practical advantages for real-world applications. This study demonstrates the effective use of DSD in optimizing adsorption parameters and underscores the potential of magnetic resin as a sustainable and efficient adsorbent for water treatment.