New chemometric approaches were introduced into the high performance liquid chromatographic (HPLC) determination of chlorzoxazone (CZX) and paracetamol (PAR) in the tablets and spiked human plasma. These chemometric approaches contain the application of classical least squares (CLS), principle component regression (PCR), and partial least squares (PLS) calibrations to the multiwavelength HPLC peak area obtained by plotting the chromatograms at the five wavelengths. The multichromatograms were obtained by using the photodiode array detector at 225 (A), 240 (B), 255 (C), 270 (D), and 285 (E) nm. The algorithms of CLS, PCR, and PLS were applied to the multichromatogram data to construct the HPLC-CLS, HPLC-PCR, and HPLC-PLS calibrations. A mixture of acetonitrile and 0.1 M ammonium carbonate (60:40, v/v) on a Waters Symmetry (R) trademark C18 Column 5 mu m 4.6 x 250 mm at a flow rate of 0.8 mL/min was used as a mobile phase to separate and determine CZX and PAR in samples. Hydrochlorothiazide (IS) was used as an internal standard in this chromatographic separation. The HPLC chemometric calibrations were successfully applied to the quantitative analysis of the investigated drugs in commercial pharmaceutical preparation and spiked human plasma samples with high precision and accuracy.