The rapid development of upconversion nanoparticles (UCNPs) has been facing with a great challenge: intense emission, fast scanning, and deep imaging require high-power light irradiation with minimized heating effect (the intrinsic 975-nm excitation of Yb3+-sensitized UCNPs have overheating problem). By shifting the excitation peak from 975 nm to 795 nm, Nd3+-Yb3+ cascade sensitized upconversion nanoparticles (Nd-UCNPs) with minimized heating effect were reported as the new generation UCNPs. For the first time, within two optically modeled applications in vitro and in vivo, the damage outcomes under long time high power laser excitation were solidly calculated, complementing the damage-free study of Nd-UCNPs. The higher resolution (20% improvement) and five times faster scanning microscopy were successfully performed using Nd-UCNPs under safety laser power level. The computational results showed the Nd3+-Yb3+ energy transfer efficiency would not compromise the deep imaging ability, and the red (650-nm) emission is worth to be enhanced for deep tissue imaging.