The effectiveness and safety of drugs may be compromised by the degradation of APIs during preparation processes or after they have been released to market. This study has investigated the degradation of 500‐mg Acetaminophen tablet (C8H9NO2) when stored under unfavorable conditions such as increased temperature and high levels of humidity. To quantify the amount of API, the Raman intensity variations of characteristic peaks of API and polyvinylpyrrolidone (PVP) (C6H9NO) are explored. By considering various sources of error in all experiments, the reliability of the extracted data set from Raman spectrums and the quality of results obtained using the utilized technique for predicting API is investigated at standard room temperature. The results demonstrate an acceptable precision in the range of pharmacopeia monograph. Then, the effect of temperature and humidity variations on the amount of API is investigated based on the related Raman spectra. The results show that the API's quantity starts to decrease after about 60 min at the temperature of 45°C ± 2°C and the relative humidity (RH) of 75% ± 2%. According to our results, when tablets are kept under the unfavorable conditions, the degradation pattern of API follows a logarithmic trend.