Upconversion nanoparticles (UCNPs) are under consideration for their use as bioimaging probes with enhanced optical performance for real time follow-up under non-invasive conditions. Photostable and core-shell NaYF4:Yb3+, Er3+-SiO2 UCNPs obtained by a novel and simple co-precipitation method from lanthanide nitrates or oxides were herein synthesized for the first time. The sol–gel Stöber method followed by oven or supercritical gel drying was used to confer biocompatible surface properties to UCNPs by the formation of an ultrathin silica coating. Upconversion (UC) spectra were studied to evaluate the fluorescence of UCNPs upon red/near infrared (NIR) irradiation. ζ-potential measurements, TEM analyses, XRD patterns and long-term physicochemical stability were also assessed and confirmed that the UCNPs co-precipitation synthesis is a shape- and phase-controlling approach. The bio- and hemocompatibility of the UCNPs formulation with the highest fluorescence intensity was evaluated with murine fibroblasts and human blood, respectively, and provided excellent results that endorse the efficacy of the silica gel coating. The herein synthesized UCNPs can be regarded as efficient fluorescent probes for bioimaging purposes with the high luminescence, physicochemical stability and biocompatibility required for biomedical applications.