The main objective of factorial design is to construct an empirical model to understand complex phenomena such as a purification process up to a given level of accuracy. The present study aimed to investigate the adsorption of Neutral Red dye (NR) from an aqueous solution onto sepiolite using 24 full factorial design. The combined effect of initial dye concentration, adsorbent dosage, pH, and particle size on adsorption of the dye was studied. The results were analyzed statistically using the student’s t-test, analysis of variance (ANOVA), and an F-test to define important experimental factors and their relative levels of importance. A regression model which may be used to estimate the removal efficiency of NR without performing any experiments was suggested. The coefficient of determination (R2 = 0.9938) indicated that <1% only of the total variations remain unexplained by the regression model. The experimental factors selected were determined to influence the adsorption process, but their relative importance varied according to the following sequence: pH > adsorbent dosage > particle size > initial concentration. The magnitude of the effects measured in this work can be used as a guide for how to adapt the adsorption process for different process conditions. The results also indicated that natural sepiolite is a suitable adsorbent for NR.