The work aims to comprehensively study the migration risk of the multi-layer composite packaging for food contact with food contact paper/aluminum/plastic composite packaging as the research object in combination with the non-targeted high-throughput screening technology and the safety risk assessment method. With headspace gas chromatography tandem mass spectrometry, gas quadrupole time-of-flight mass spectrometry and liquid quadrupole time-of-flight mass spectrometry, the volatile, semi-volatile and non-volatile migration substances of paper/aluminum/plastic composite packaging for food contact were comprehensively screened under different migration conditions. Then, based on commercial databases, laboratory self-built databases and industry information, the chemical structure and possible sources of substances were analyzed. According to the semi-quantitative results of internal standards, the compliance evaluation and risk characterization of the migratory substances were carried out with domestic and foreign regulations on food contact materials and safety risk assessment methods. The results showed that in 20 batches of paper/aluminum/plastic composite packaging for food contact, no migration risk was detected in the 4% acetic acid simulants. A total of 35 substances were detected in the 95% ethanol simulants, which may come from solvents, antioxidants, smoothing agents, oligomers and antioxidant oxidation/degradation products. Among them, 33 substances showed low risks, but the other two monomer oligomers were recommended to continue to pay attention to the progress of toxicological research and the dynamic change of domestic and foreign laws due to their unknown structures and incomplete toxicological research. Therefore, with the combination of non-targeted high-throughput screening technology and safety risk assessment methods, there is no safety risk found in using paper/aluminum/plastic multi-layer composite packaging for containing water-based foods such as fruit juice under normal usage conditions. However, it is still necessary to pay attention to the migration safety of polyolefin oligomers when the packaging was exposed to the foods with high ethanol or fat content.