The capabilities of desorption electrospray ionization-high resolution mass spectrometry (DESI-HRMS) were tested for screening the presence of some paralytic shellfish toxins in clams. A quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach is proposed for sample clean-up. QuEChERS extraction was optimized by using a full factorial design followed by the multicriteria method of the desirability functions. Quantitation limits in the microgram per kilogram range proved reliability of the method for the detection of the investigated toxins in accordance to the rules laid down by European legislation. The optimized QuEChERS-DESI-HRMS based-method allowed for a rapid reliable screening of the investigated compounds at levels of interest, thus being useful for high-throughput analyses.