This study concerns the simultaneous detection of five rare-earth elements (REEs) – Ce, La, Nd, Pr, Sm – in ores and nodules using two X-ray fluorescence techniques (XRF): total reflection (TXRF) and wavelength-dispersive (WDXRF). The issues of high pairwise correlation between REE contents in certified reference materials of natural origin, resulting in a poor quality of calibration sample set, and the significant overlapping of REE lines, especially in TXRF spectra, which have low spectral resolution, are addressed in the study. For the first time, this is done by employing a specially designed calibration set, based on Latin hypercube sampling. Its applicability was assessed for univariate and multivariate (PCR, PLS) calibration models to overcome the above issues. A feature of our calibration set is the use of artificial mixtures of REE oxides and Fe₂O₃ + TiO₂ (as a matrix) providing extremely low correlation (<0.03) between the content of different REEs. Simultaneously, the validation set consists of natural certified reference materials of REE-rich ores and oceanic ferromanganese nodules. The content of each REE in the calibration set varies in the range of 0–40 000 ppm. Our PLS/PCR-based calibration models provide a quantitative determination of Ce, La, and Nd content using both XRF techniques. Pr and Sm were special cases, which cannot be quantitatively determined using univariate calibration, while our multivariate models were able to detect these REEs at a level above 100 ppm.