Photodynamic therapy has advantages over conventional cancer superficial tumor therapies, such as insignificant side effects, minimal cumulative toxicity, excellent functional and cosmetic results, precise target treatment minimizing damage to neigh-boring normal tissues, and optimum long-term tumor regression. Upconversion nanoparticles have been proposed to extend photodynamic therapy for treating non-superficial tumors. In particular, compounds with low phonon energy, like KMgF3, with an optimal synthesis design and a suitable doping system, could be used for this therapy application. This particular matrix allows the incorporation of dopants as transition metals ions (as Mn2+) besides rare-earth elements, minimizing the use of the former. To obtain nanoparticles of suitable size for nanomedicine, we used a factorial experimental design to determine statistical synthesis conditions that significantly affect particles’ size. With the proposed synthesis method, it was possible to obtain KMgF3 nanoparticles with sizes ranging from 13.46±0.30 nm to 32.18±0.60 nm, values estimated with the XRD technique and with size distribution suitable for photodynamic therapy. We proved the good correlation between the particle size estimated from transmission electron microscopy images and powder X-ray diffraction measurements. According to the statistical analysis, the temperature and the interaction of temperature with MgCl2 concentration significantly affect the particle size (significance level of 0.05). The present work describes the influence of solvothermal synthesis parameters on the KMgF3 nanoparticle size for the first time. The results are particularly interesting for further doping the system and its functionalization, foreseeing the final application in cancer treatment.