A novel method based on online turbulent flow chromatography (TFC) combined with liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been established for simultaneous quantitative determination of 11 lipophilic marine toxins (OA, DTX1, DTX2, YTX, hYTX, AZA1, AZA2, AZA3, PTX2, SPX1, and GYM) in shellfish. Sample preparation, including extraction with 75% methanol aqueous solution, centrifugation, and filtration, was followed by online cleanup using TFC. The total run time was within 15.5 min, including online purification, chromatographic separation, and re-equilibration of the TFC system. Various experimental parameters including extraction, purification, separation, and detection were optimized separately in this study. The developed method was validated, and good performance characteristics were obtained. The linear regression coefficients (R2) of matrix-match calibration standard curves established for quantification were higher than 0.9945. The limits of detection and quantification of this method ranged between 0.5 and 4.0, and 1.5 and 10.0 µg/kg, respectively. The average recoveries of spiked target compounds with different concentrations ranged from 80.1 to 113.8%, the intra- and inter-day precision were lower than 12.7% and 14.9%, respectively. The matrix effects were in the range of 76.1–115.9%. The method accuracy was also confirmed with certified reference materials. The results indicate that the developed method has great potential for the routine laboratory analysis or emergency detection of lipophilic marine toxins in shellfish.