A simple, rapid, cost-effective, and eco-friendly method is proposed for the simultaneous determination of some common over-the-counter drugs (aspirin, paracetamol, and caffeine [APC]) in saliva and pharmaceutical formulations based on the coupling of ultrasound-assisted emulsification microextraction (USEME) with thin-layer chromatography (TLC)‒image-processing analysis. The process involves the rapid injection of 65 μL of chloroform in diluted saliva samples (2 mL) followed by ultrasonication, which results in the formation of an emulsion. This solution is centrifuged, and 20 μL was spotted on TLC plate which was allowed to develop in mobile phase of ethyl acetate and acetic acid (95:5, v/v). The developed TLC plate was photographed, and the spots of APC were quantified by using the freely available ImageJ software (National Institute of Health [NIH], Bethesda, MD, USA). Factors which can influence the yield of USEME were screened using 27‒4 Placket–Burman design (PBD), and significant factors were optimized using central composite design (CCD). The recoveries and detection limits for all the analytes were found to be in the range of 89.2–94.1% and 0.007–0.012 mg spot−1, respectively. The assay was found to be linear in the range of 0.04–0.2 mg spot−1 with correlation of coefficient of 0.990–0.994. Intra- and inter-day precision for the assay were found to be in the range of 3.12–4.93% and 5.66–8.61%, respectively. The developed method does not require any special instrument and handling skill for the quantitative analysis of APC in saliva and pharmaceutical formulations.