In recent years, infrared emitting luminescent nanothermometers have attracted significant attention because their potential for the development of new diagnosis and therapy procedures. Despite their promising applications, concerns have been raised about their reliability due to the spectral distortions induced by tissues that are present even in the commonly used second biological window (1000–1370 nm). In this work, we present an innovative solution to this issue by demonstrating the effectiveness of shifting the operation range of these nanothermometers to the third biological window (1550–1850 nm). Through experimental evidence using ytterbium, erbium, and thulium tri-doped CaF2nanoparticles, we demonstrate that luminescence spectra acquired in the third biological window are minimally distorted by the presence of tissue, opening the way to reliable luminescence thermometry. In addition, advanced analysis (singular value decomposition) of emission spectra allows sub-degree thermal uncertainties to be achieved.