A simple and rapid UV derivative method with zero-crossing determinations was developed for estimation of acetaminophen (ACE) and caffeine (CAF) in fixed-dose combination formulations. The first-derivative of standard solutions of both drugs were used and ACE and CAF were quantified at 273.0 and 216.5 nm, respectively. The method was validated, and it was applied to dissolution studies with the USP Apparatus 2 and flow-through cell (USP Apparatus 4). Dissolution profiles comparisons (generic vs reference) were carried out with model-independent and model-dependent approaches. Mean dissolution time and dissolution efficiency were calculated and significant differences, in almost all calculated parameters, were found (p<0.05). Weibull, logistic, Gompertz, and Probit models were used to fit dissolution data and Probit was the best-fit model that describes the in vitro dissolution performance of ACE and CAF. Using t50% data, derived from this fit, dissolution profiles of ACE in USP Apparatus 2 were significant different (p<0.05). The proposed UV derivative method generates reliable information that can be compared with published results. Dissolution studies of fixed-dose combination formulations are important because quality of generic drug products depends on quality of references. It is essential to maintain a post-marketing evaluation of formulations with analgesic drugs mixed with CAF to offer the population high quality medicines.