Over-the-counter medications (OTCMs) are frequently recommended as a first-line treatment for common ailments, diseases, and illnesses. Oral liquid dosage forms are advantageous for rapid absorption with no dissolution time and are easier for pediatric and geriatric consumers to swallow. The production of these medicines by pharmaceutical industry makes them readily available to the public. Although the US Food and Drug Administration (FDA) provides strict guidelines to drug manufacturers of these products; the risk of counterfeiting is a global issue. This can lead to several adverse effects and health issues. Here, we report a fast screening and quality assurance method using Raman and UV–visible spectroscopy combined with Principal Component Analysis (PCA) and Partial-Least-Square (PLS) regression of commonly used OTCM oral syrups. PLS regressions of UV–visible absorption spectra were used for multicomponent quantifications of the active component (acetaminophen, guaifenesin, dextromethorphan HBr, and phenylephrine HCl) concentrations of OTMCs in flavored (sugar or sugar-free) oral syrups. Raman and UV–visible spectral responses varied based on the type and concentration of the active component analyzed. PCA of the spectral data provided pattern recognition of the oral syrup OTCM. The developed PLS method demonstrated good linearity with an R2 > 0.9784 and high sensitivity with a low detection limit of 0.02 mg/mL for acetaminophen and guaifenesin. Moreover, the simultaneous quantification of concentrations of all active components by the described method yielded good accuracies ranging from 88 to 94%. This study provides an example of the benefits of the combined use of Raman and UV–vis spectral profiling, PCA, and PLS regression for the quality analysis of oral syrups OTCM providing multicomponent quantification of active components with no need for sample extraction. The reported method can be easily adapted and scaled for online detection analysis used in the drug manufacturing industry, both in-situ and field analysis, and for the quality control of syrups OTCM by regulatory agencies and quality control officers.