Two ultraviolet (UV)–spectrodensitometric methods were proposed for the separation and determination of binary and ternary mixtures containing proton pump inhibitors (PPIs). Method A was developed for the assay of omeprazole, panoprazole, rabeprazole, and lansoprazole in binary mixtures with domperidone (DOM) using their isoabsorptive points. Method B was developed for the determination of a ternary mixture containing omeprazole, tinidazole, and clarithromycin. It depends on using malonic acid–acetic anhydride as a spraying reagent to form yellow color (for omeprazole) and dark brown color (for clarithromycin) that are measured at λmax = 350 nm and λmax = 492 nm, respectively, while tinidazole was measured by UV at λmax = 310 nm. For method A, Beer’s law was obeyed for all studied PPIs and domperidone in the concentration range of 180–1440 and 120–720 ng spot−1, respectively. The detection limits for proton pump inhibitors and domperidone were 48.05–73.45 and 30.74–32.50 ng spot−1, respectively, and the quantitation limits were 145.59–222.47 and 93.14–98.48 ng spot−1, respectively. For method B, Beer’s law was obeyed for omeprazole, clarithromycin, and tinidazole in the concentration range of 180–480, 2250–6000, and 30–180 ng spot−1, respectively. The detection limits for omeprazole, clarithromycin, and tinidazole were 20.36, 272.60, and 2.05 ng spot−1, respectively, and the quantitation limits were 61.7, 825.9, and 6.2 ng spot−1, respectively, for the investigated drugs.