This study was performed to determine the effect of tannic acid (TA) on hydrophobicity of galena using Taguchi’s design of experimental methodology. Roles of metal ions, dithiophosphinate (DTPI) concentration, and conditioning time on TA-galena interaction were tested by contact angle measurements. Results were evaluated by analysis of variance (ANOVA) test. DTPI was found to be the most effective parameter on the hydrophobicity followed by TA and nobility of metal ions. Effect of conditioning time was statistically insignificant. Electrochemical activity of metal ions became effective on TA-galena interaction: more active metals exhibit synergic effect with TA on the hydrophilicity of galena whereas more noble metals reduced the adverse impact of TA. Taguchi’s design revealed that interactions between experimental variables were not statistically significant.