This study synthesized peptide-functionalized Lu and Sm sesquioxide nanoparticles by precipitation-calcination (P–C) and pulsed laser ablation in liquids (PLAL) to evaluate their physicochemical properties after neutron activation. Nanoparticles were obtained by precipitation in an alkaline solution, followed by centrifugation, drying, calcination, and functionalization with peptides (three or eighteen amino acids). For the PLAL nanoparticle synthesis, tablets made of Lu2O3 and Sm2O3 powders were immersed in peptide solutions and laser-irradiated (Nd:YAG) for 30 min, followed by ultracentrifugation as a purification process. The nanosystems were analyzed using transmission electron microscopy, high-resolution transmission electron microscopy, selected area electron diffraction, X-ray diffraction, differential scanning calorimetry-thermogravimetry, and FTIR and UV–Vis spectroscopies. Luminescence was evaluated after nanoparticle neutron activation using an optical imaging device (CCD camera). The Lu2O3 and Sm2O3 nanoparticles synthesized by P–C showed a quasi-spherical and well-defined morphology, with a monomodal and monodispersed size distribution (30.05–44.83 nm) and highly crystalline patterns (cubic m3‾ space group). In contrast, the micrographs of the Lu and Sm sesquioxide nanoparticles obtained by PLAL showed two distinct populations, namely, one of well-defined and dispersed spherical particles (62.35–75.02 nm), and the other of precursor material fragments without defined form or size (>2 μm). The diffractograms of the PLAL synthesis products were wide and not well defined due to the amorphous material that was simultaneously produced with the crystalline nanoparticles, which affected the detection of luminescence. The nanosystems prepared by P–C were obtained in high yields (70% for Lu2O3 and 90% for Sm2O3) and with optimal physicochemical characteristics, significantly impacting the radioluminescence properties of the nanoparticles (emissions of ∼615 nm for Lu2O3 and ∼758 nm for Sm2O3). P–C is a suitable method for producing peptide-functionalized 177LuLu and 153SmSm sesquioxide nanoparticles for dual imaging (nuclear and optical imaging) in potential theranostic applications. Display omitted •Precipitation-calcination-synthesized Lu and Sm sesquioxide nanoparticles show highly crystalline patterns.•Precipitation-calcination-synthesized Lu and Sm sesquioxide nanoparticles are radioluminescent after neutron activation.•Amorphous material was co-produced with crystalline pulsed laser ablation-synthesized Lu and Sm sesquioxide nanoparticles.•Pulsed laser ablation-synthesized Lu and Sm sesquioxide nanoparticles are not radioluminescent after neutron activation.