The formation and disappearance of aldehydes during simulated gastrointestinal digestion (SD) of fried clams was investigated in order to shed light on the underlying mechanism. Results from the thiobarbituric acid reactive substance (TBARS) and fluorometric assays using a specific aldehyde probe indicated that the SD (with lipase) of fried clams initially reduced (at the gastric stage), but subsequently increased (mainly at the intestinal stage) the contents of total aldehydes. Meanwhile, eight specific aldehydes including propanal, acrolein, trans-2-pentenal, hexanal, trans,trans-2,4-octadienal, trans,trans-2,4-decadienal, 4-hydroxy-hexenal and 4-hydroxy-nonenal in the digested meal were determined by using a high-performance liquid chromatography-tandem electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method. Results indicated that the changes in the trend of the contents of the eight aforementioned aldehydes were similar to those of total aldehydes during SD (with lipase) of fried clams. However, a similar SD process without lipase time-dependently reduced the contents of total and individual aldehydes. Moreover, lipid classes and free fatty acids (FFAs) in the digested meal were determined to reveal the degree of hydrolysis of lipids during the SD process. Results indicated that the SD (with lipase) of fried clams significantly hydrolyzed triacylglycerols (TAG) and polar lipids (PL) and produced FFAs, but the SD process without lipase resulted in negligible lipid hydrolysis. Thus, our results demonstrated a positive correlation between lipid hydrolysis and aldehyde generation during the SD of fried clams. Alternatively, unsaturated FFAs instead of TAG and PL could have served as the main precursors for aldehyde generation due to their high oxidative susceptibility.