Green, simple, accurate and robust univariate and chemometrics assisted UV spectrophotometric approaches have been adopted and validated for concurrent quantification of fluocinolone acetonide (FLU), ciprofloxacin HCl (CIP) together with ciprofloxacin impurity-A (CIP imp-A) in their ternary mixture. Double-divisor ratio spectra derivative (DDRD) method has been used for determination of FLU. On the other hand, the first (D1) and second (D2) derivative approaches have been applied for the quantification of CIP and CIP imp-A, respectively. For the ratio difference (RD), derivative ratio (DR), and mean centering of ratio spectra (MC) methods, CIP and its impurity A have been simultaneously determined. The acquired calibration plots were linear over the concentration range of 0.6–20.0 μg/mL, 1.0–40.0 μg/mL and 1.0–40.0 μg/mL for fluocinolone acetonide, ciprofloxacin HCl, and ciprofloxacin impurity-A, respectively. The chemometrics methods namely; partial least squares (PLS) and artificial neural networks (ANN) were used for the concurrent determination of the three adopted components via using twenty-five mixtures as calibration set and fifteen mixtures as validation one. The investigated approaches were validated in accordance with International Council for Harmonisation (ICH) guidelines, and statistically compared with the official ones. The proposed methods were acceptably applied to the examination of FLU and CIP in their pure powders and pharmaceutical ear drops.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13065-023-00963-w.