An optimized method for the determination of five synthetic polycyclic: celestolide (ADBI), phantolide (AHMI), traseolide (ATII), galaxolide (HHCB), tonalide (AHTN), and two nitro-aromatic musks: musk xylene (MX) and musk ketone (MK), in water samples is described. The method involves a dispersive micro solid-phase extraction (D-μ-SPE) plus ultrasound-assisted solvent desorption (UASD) prior to their determination by gas chromatography-mass spectrometry (GC-MS) using the selected ion storage (SIS) mode. Factors affecting the extraction efficiency of the target analytes from water samples and ultrasound-assisted solvent desorption were optimized by a Box-Behnken design method. The optimal extraction conditions involved immersing 10.1 mg of a typical octadecyl (C18) bonded silica adsorbent (i.e., ENVI-18) in a 50 mL water sample. After 10.4 min of extraction by vigorously shaking, the adsorbent was collected and dried on a filter, and the target musks were desorbed by ultrasound-assisted for 38 sec with n-hexane (200 μL) as the desorption solvent. A 10 μL aliquot was then directly determined by large-volume injection GC-MS. The limits of quantitation (LOQs) were 1.2 to 5 ng/L. The precision for these analytes, as indicated by relative standard deviations (RSDs), were less than 11% for both intra- and inter-day analysis. Accuracy, expressed as the mean extraction recovery, was between 74% and 92%. A preliminary analysis of the effluents from municipal wastewater treatment plants (MWTP) and river water samples revealed that HHCB and AHTN were the two most commonly detected synthetic musks; their concentration were determined to range from 88 to 690 ng/L for effluent samples, and 5 to 320 ng/L for river water samples. This is a simple, low cost, effective, and eco-friendly analytical method.