ABSTRACT Traces of medicinal formulations and their metabolites often remain in animal products. The presence of nonsteroidal anti‐inflammatory drugs (NSAIDs) in food is a factor in chronic human health effects. Therefore, improved methods for their determination are needed for food safety. Usually, a complex sample preparation based on enzymatic, alkaline, or acidic hydrolysis is applied to recover residual NSAIDs from their hydroxyl‐, carboxyl‐, glucuronide‐, and other derivatives to the original forms. This work reports on a systematic study and comparison of the sample preparation of real samples for the determination of NSAIDs and their metabolites. The objects of analysis were meat and by‐products obtained from chickens that were treated with preparations containing metamizole, diclofenac, ketoprofen, ibuprofen, meloxicam, phenylbutazone, and mefenamic acid with their feed. The effects of acidity of the extraction solution, glucuronidase enzyme, and different sorbents for purification by solid‐phase extraction were studied. The hydroxyl‐ and carboxyl‐metabolites were detected by HPLC–MS/MS. It was shown that the long hydrolysis step during the sample preparation can be replaced with extraction into acetonitrile, making the full analytical procedure “whiter.”