Abstract Quantitative multicomponent analysis is considered an analytical goal to save time and cost in analysis. Hence, this work aimed to provide sensitive and selective UV-spectrophotometric, chemometric manipulation, and ultra-performance LC (UPLC) methods for the determination of well-known coformulated antiemetics used in pregnancy, namely pyridoxine HCl (PYR), meclozine HCl, and cyclizine. The developed UV-spectrophotometric methods are dual wavelength in ratio spectra and first derivative of the ratio spectra with which PYR was determined selectively at 290.8 nm, whereas the other drugs in a ternary mixture were determined from their ratio spectra using a spectrum of PYR as a divisor in 0.1 M HCl. An ecofriendly partial least-squares regression chemometric method was applied to raw UV absorbance data for the determination of the ternary mixture in a 218–355 nm range using a three-factor, three-level design with water as the green solvent. A gradient UPLC method was developed and successfully resolved the ternary mixture within 5 min. Different ratios of water (adjusted to pH 3 with phosphoric acid) and methanol were delivered at 0.5 mL/min as the mobile phase into a Hypersil Gold C18 column (50 × 2.1 mm, 1.9 µm). The developed methods were successfully applied to different pharmaceutical formulations containing the aforementioned drugs and validated according to the International Conference on Harmonization guidelines. The results obtained were reproducible and reliable and can be applied for routine analysis and QC in laboratories.