Antidepressant drugs are widely used in the treatment of different psychiatric disorders, as well as in conjunction with antipsychotics for the treatment of major depressive disorder. In this study, a simple and rapid ultrasound-assisted low-density solvent dispersive liquid–liquid microextraction (UA-LDS-DLLME) method was developed for the simultaneous determination of 12 new antidepressants (norfluoxetine, fluoxetine, fluvoxamine, agomelatine, mirtazapine, moclobemide, melitracen, N-desmethylmirtazapine, maprotiline, sertraline, citalopram, paroxetine) and 2 antipsychotics (clozapine and haloperidol) in human whole blood by gas chromatography–mass spectrometry (GC–MS). Different parameters affecting the UA-LDS-DLLME were optimized and the optimal conditions were as follows: 100 μL of toluene as extraction solvent, extraction pH 12 and 3 min of ultrasound stirring. Good linearity (R2 ≥ 0.991) was obtained at the concentration range of 15–1500 ng/mL for norfluoxetine, fluoxetine, fluvoxamine, melitracen, maprotiline and citalopram, and 5–500 ng/mL for agomelatine, mirtazapine, moclobemide, N-desmethylmirtazapine, sertraline, paroxetine, clozapine and haloperidol. The intra-day and inter-day precision were all less than 10%, and accuracy of intra-day and inter-day were in the range of −12.7% to 7.9% and −13.9 to 11.8%, respectively. The extraction recoveries of most analytes were more than 60%. The UA-LDS-DLLME/GC–MS method was demonstrated with acceptable precision, accuracy and good specificity for the simultaneous determination of 12 antidepressants and 2 antipsychotics, and has been successfully applied in a real case.