In this study, different metal cations such as Ag+, Pd2+, Mn2+, In3+, Au3+, and Bi3+ were removed from a solid matrix using supercritical CO2 containing cyanex 301 as a ligand. When the solvating power of supercritical CO2 is combined with the metal ion complexing power of an organic ligand, a clean alternative to conventional liquid-liquid and liquid-solid extraction is obtained. An orthogonal array design (OAD), OA(9) (3(4)), was employed as a chemometric method for the optimization of the supercritical fluid extraction (SFE) of metal cations from a solid matrix. Four parameters, namely, the pressure and temperature of the supercritical fluid, the dynamic extraction time, and the volume of modifier, were studied and optimized by a three-level OAD in which the interactions between the parameters were temporarily neglected. To optimize the SFE condition for each cation, nine experiments were performed in random order. Determinations of the extracts were performed by atomic absorption spectroscopy. The effects of parameters were studied using analysis of variance (ANOVA). The results showed that Ag+, Pd2+, Mn2+, In3+, Au3+, and Bi3+ could be effectively extracted from the solid matrix by using supercritical fluid extraction and cyanex 301 as a chelating agent. Finally, the experimental conditions providing the highest extraction yield inside the experimental domain considered were proposed.