The effects of organic solutions on the stability and extraction equilibrium of penicillin G were investigated. N-Butyl acetate, methyl isobutyl ketone, 2-ethyl hexanol, kerosene, and n-heptane were used for physical extraction; di-N-octylamine, tri-N-octylamine, N235 (a mixture of tertiary amines), tributyl phosphate, and di-(2-ethylhexyl)phosphoric acid were used as the extractants, with N-butyl acetate, kerosene, and n-heptane as diluents for reactive extraction. The degradation efficiency of penicillin G increases with increasing temperature. The stability of penicillin G was better in the presence of an amine-based extractant, while it was worse in the presence of a phosphorus acid extractant. The effect of neutral extractant on the stability of penicillin G was mainly dependent on the temperature. The degradation of penicillin G in alkali solution was governed by The efficiency of physical extraction of penicillin G increased with decreasing pH in the aqueous solution. The efficiency of reactive extraction with an amine-based extractant was highest under the range studied. The extractant of phosphorus acid was better than neutral phosphorus extractant for the extraction of penicillin G. The distribution coefficient decreases with increasing pH, temperature, and initial penicillin G concentration in the aqueous solution under the studied conditions. The mechanism of degradation and extraction was also discussed.