<p>A versatile RP-HPLC method using phenyl–hexyl stationary phase and gradient elution (0.1% aqueous acetic acid and methanol) was developed to investigate the chemical integrity of twelve historical analgesic single- and multi-component preparations (1940s to 1990s). UV–Vis detection, supported by tandem mass spectrometry, was employed for compound identification and potential degradation product screening. Twelve active pharmaceutical ingredients (APIs)—including acetylsalicylic acid, bromisoval, caffeine, codeine, narcotine, phenacetine, phenobarbital, salicylic acid, and four distinct barbiturates—were investigated. Calibration models were established with limits of quantification as low as 3.0&#xa0;mg&#xa0;dm^–3. Coelution of phenobarbital and aminophenazone was effectively resolved through mathematical correction using dual-wavelength detection. Most APIs demonstrated remarkable long-term stability (within ± 10% of declared content), with the exception of codeine and acetylsalicylic acid in specific preparation. Effervescent and poorly stored tablets exhibited significant degradation, highlighting the importance of dosage form and storage conditions. In addition, the tandem mass spectrum of bromisoval is presented here for the first time in the literature, and a plausible fragmentation mechanism is proposed.</p> Graphical Abstract <p></p>