Acetaminophen (APP), frequently used as analgesic and antipyretic drug in our life, is potentially toxic to both animals and humans. A novel acetaminophen degrading strain HZA2, was isolated from the activated sludge, and identified as Shinella sp. based on its 16S rRNA gene sequence analysis, morphological, physiological, and biochemical characterizations. This strain could degrade 100 mg L−1 acetaminophen completely within 12 h, and it was also a very effective strain for the degradation of high concentration of acetaminophen below 3000 mg L−1 under the optimal condition. The optimal degrading conditions of acetaminophen by HZA2 were pH 7.5 and 32.7 °C by the analysis of response surface methodology. Exogenous carbon source could enhance the biodegradation of acetaminophen. During the process, the intermediate metabolites were identified as 4-aminophenol and hydroquinone via gas chromatography-mass spectrometry analysis. The results indicated that strain HZA2 may be a promising bacterium for the bioremediation of acetaminophen pollutions.