Monitoring medications in biological fluids is an essential aspect of patient care, particularly in cases of altered mental status where accurate diagnosis, effective treatment, and even forensic examinations are crucial. In this study, a new approach combining hydrophobic-deep-eutectic and solvent-bar-microextraction (HDE-SBME) followed by a high-performance liquid chromatography-diode array detector (HPLC-DAD) was developed for the simultaneous determination of desipramine, clomipramine, as antidepressant and carbamazepine as antiepileptic agents in untreated human urine and plasma samples. The HDE solvents, synthesized using various ratios of menthol and fatty acids, were utilized in the SBME setups. Computational methods were employed to predict the structure and modes of interaction between HDE and the chosen analytes. Central composite design methodology (CCD) was used for multivariate optimization of the effects of different parameters influencing the extraction efficiency of the proposed method. Under optimized experimental conditions, the calibration graph of the spiked selected drugs in urine and plasma samples demonstrated excellent linearity (R2 ≥ 0.994), with limits of detection/quantification below 0.60/2.02 μg L−1. The extraction recoveries achieved were 88–97%, and the repeatability/reproducibility (RSD%, n = 5) was less than 6.12/7.57. The proposed method was successfully applied to determine selected drugs in patients' urine and plasma samples. The proposed method detects three drugs in patients' urine and plasma samples without using toxic volatile organic solvents. The proposed microextraction technique exhibited a confident sensitivity, feasible operation, and simplicity compared with other published methods. Thus, it can be considered a promising method for monitoring the therapeutic levels of specific antidepressant and antiepileptic drugs in urine and plasma samples.