A spectrofluorimetric method has been developed for the quantitative determination of mefenamic, flufenamic, and meclofenamic acids in urine samples. The method is based on second-order data multivariate calibration (unfolded partial least squares (unfolded-PLS), multi-way PLS (N-PLS), parallel factor analysis (PARAFAC), self-weighted alternating trilinear decomposition (SWATLD), and bilinear least squares (BLLS)). The analytes were extracted from the urine samples in chloroform prior to the determination. The chloroform extraction was optimized for each analyte, studying the agitation time and the extraction pH, and the optimum values were 10 minutes and pH 3.5, respectively. The concentration ranges in chloroform solution of each of the analytes, used to construct the calibration matrix, were selected in the ranges from 0.15 to 0.8 microg mL-1 for flufenamic and meclofenamic acids and from 0.25 to 3.0 microg mL-1 for mefenamic acid. The combination of chloroform extraction and second-order calibration methods, using the excitation-emission matrices (EEMs) of the three analytes as analytical signals, allowed their simultaneous determination in human urine samples, in the range of approximately 80 mg L-1 to 250 mg L-1, with satisfactory results for all the assayed methods. Improved results over unfolded-PLS and N-PLS were found with PARAFAC, SWATLD, and BLLS, methods that exploit the second-order advantage.