Two sensitive and accurate methods UPLC−MS and UV−spectrophotometry were adopted for the determination of ketoprofen simultaneously in two binary mixtures with the phosphate salts of either tilmicosin or tylosin. UPLC−MS method was applied to conduct efficient separation of the drugs. For ketoprofen, R2=0.9999 was obtained over the concentration range of 0.5−5.0 ng mL−1. While the range of 1.0−10.0 ng mL−1 for each of tilmicosin and tylosin showed correlation coefficients of 0.9999 and 0.9998, respectively. Four UV−spectrophotometric methods; dual wavelength, mean centering, ratio difference and ratio derivative methods were adopted for the determination of these drugs in propylene glycol. For the UV−spectrophotometric methods, the estimated linearity ranges for ketoprofen (2.0−30.0 µg mL−1) and both tilmicosin and tylosin (5.0−100.0 µg mL−1) showed excellent correlation coefficients. UPLC−MS and UV−spectrophotometric methods were validated following ICH guidelines. It is noteworthy that the two techniques are the first to be developed for the simultaneous quantification of Ketoprofen along with tilmicosin, or tylosin, in both bulk and two new veterinary formulations Ketotilmizide ® and Painless Plus ®. Furthermore, the proposed UPLC−MS method was utilized efficiently for the simultaneous estimation of a binary mixture of ketoprofen with either tilmicosin or tylosin in spiked biological poultry plasma samples.