A natural Moroccan illite-smectite clay was investigated as adsorbent of nickel in water. Before its use, it was processed without additives as honeycomb monoliths, an advantageous design in many methods developed to control environmental pollution. The performance of the resulting monoliths was studied in dynamic conditions by flow recirculation through the honeycombs and using Atomic Absorption Spectroscopy for the determination of residual nickel concentration in the solutions. Design of experiments (DoE) was employed to evaluate the influence of three parameters and their interaction on the nickel adsorption capacity of the clay honeycombs: nickel concentration (10–206 ppm), salt concentration (4–36 g/L), and water flow (94–364 mL/min). Based on previous studies, recirculation time, pH and temperature were fixed at 1 h, 4.5 and room temperature, respectively. The maximum amount of nickel adsorbed (0.83 mg/g of clay) was obtained for a nickel concentration of 206 ppm, a 218 mL/min flow, and a salt concentration of 4 g/L. Experimental conditions for the highest repeatability were estimated, the respective values being 108.2 ppm, 94 mL/min and 20 g/L. Nickel retention by the clay was also confirmed after the adsorption tests by direct characterization of the used structured adsorbent through X-ray Fluorescence and SEM-EDS.