Rare earth ion-doped Y2O3 nanoparticles are attractive for biological imaging applications due to their non-toxicity, resistance to photobleaching, and possibility for upconversion. Y2O3:Yb3+/Tm3+ nanocrystals display photoluminescence (PL) with a peak at ~811nm if excited at ~980nm. This Near-Infrared to Near-Infrared (NIR-to-NIR) upconversion (UC) process provides deeper light penetration into biological specimen and results in high contrast optical imaging due to absence of an autofluorescence background and decreased light scattering. Here, we report that NIR-to-NIR UC PL intensity of Y2O3:Yb3+/Tm3+ nanocrystals are enhanced by doping with different Tm3+ ions and Li+ ions concentration. When the Tm3+ ions concentration reaches 0.25 mol%, the NIR-to-NIR UC PL intensity is the strongest. And the NIR-to-NIR UC PL intensity of Y2O3:5 mol % Yb3+ ions, 0.25mol% Tm3+ ions and 5mol% Li+ ions is maximum, which is more that about 14 times than that of no doped Li+ ions. This material may show promise for use as probes for biological imaging.