Mass spectrometry imaging (MSI) is a powerful molecular imaging technique that enables the visualization of the spatial distribution of a wide range of molecules in food. However, certain key components within food matrices are difficult to detect directly owing to their low abundance, poor ionization efficiency, or chemical instability. On-tissue chemical derivatization (OTCD) techniques have emerged as a critical strategy to enhance the analytical performance of MSI. By introducing specific functional groups in situ, OTCD significantly improves the ionization efficiency, detection sensitivity, and stability of target molecules. This review provides a systematic overview of OTCD techniques for MSI, focusing on the derivatization reaction mechanisms for various functional groups (such as amines, carboxylic acids, and carbonyl compounds), derivatization methods (such as, spray-based methods, microdroplet deposition, and carrier-mediated delivery), and recent advances in mapping functional component distributions in food, monitoring drug metabolism, and imaging harmful substances. Finally, the future development directions of these techniques within the food sector are discussed, highlighting potential applications in the design and development of novel derivatization reagents, artificial intelligence-assisted reaction optimization, and multi-target parallel derivatization analysis. Overall, this review provides valuable insights and methodologies to advance the quality and capabilities of MSI through OTCD.