Aflatoxin M1 (AFM1) and patulin (PAT) are regulated mycotoxins, which are generally analyzed in food samples alone (“one analyte at a time”). This paper presents the development of a liquid chromatography isotope dilution tandem mass spectrometric (LC-IDMS) method for the determination of AFM1 in milk-based products, which method was then successfully applied to PAT in apple-based food samples. The method involved a selective solid-phase extraction clean-up at acidic pH employing mixed-mode cation exchange cartridges. The purification allowed the adequate adsorption of neutral target compounds and basic matrix constituents of the sample to the reversed-phase (RP) and to the cation exchange phase of the cartridge, respectively. The sample elution with pure methanol yielded an extract free from basic matrices. The remaining acidic and neutral matrix constituents of the samples were separated from the analytes using mixed-mode anion exchange HPLC column. Mobile phases without any modifiers were used for the highest sensitivity and better selectivity. The intensity enhancement obtained by neutral eluent composition was inter-laboratory tested and confirmed on same type of instruments. The sample preparation requires low amount of organic solvent, thus adhered to green analytical chemistry. The developed method for analyzing AFM1 resulted in low matrix effect of LC-IDMS separation −4.9-(−1.5%) and high precision (2.7–5.9%), calculated under method validations at spiking levels between 0.005 and 0.050 µg/kg. Method performance characteristics for analyzing PAT were also evaluated at 10 and 25 µg/kg levels. Finally, the advantageous features of the newly developed method were briefly compared and discussed with the existing approaches.