A multiple heart-cutting two-dimensional liquid chromatography (MHC-LC-LC) was coupled to quadrupole-orbitrap high resolution mass spectrometry (HRMS) to simultaneously determinate the aflatoxins (AFs) and ochratoxin A (OTA) in snus. A C18 capillary column was used as the first dimension (1D) column to isolate the AFs and OTA from the complex matrices, then a 2-position/10-port high pressure valve equipped with two 60 µL loops was employed to transfer the heart-cuts of 1D-LC into a pentafluorphenyl (PFP) column, where the second dimension separation was performed. Results of use of the MHC-LC-LC system, the ionisation suppression was noticeably reduced while the method’s sensitivity was enhanced, which is essential for trace mycotoxins analysis. With excellent capability for qualitative analyses compared to triple quadrupole mass spectrometry, the HRMS was employed to eliminate the false positives and avoid the unnecessary clean-up pre-treatment. A dynamic range of 0.2 µg/kg to 20 µg/kg was achieved with the quantification limits of 0.05 µg/kg for AFB1 and 1.0 µg/kg for OTA in dry mass of product. The results revealed that the established method exhibited good repeatabilities and recoveries, and could be used as a rapid and reliable approach for routine analysis of AFs and OTA in snus.