A series of Nd3+/Yb3+/Er3+/Li+ doped Lu2O3 nanospheres with green and red emissions are synthesized by co-precipitation method. XRD analysis indicates the doping pattern of Li+ changes from site substitution to interstitial with increased doping contents. By introducing Li+, manipulation of nanospheres diameter, up-conversion luminescence (UCL) enhancement and green to red emission ratios adjustment are achieved simultaneously. In-depth UCL modulation mechanisms are investigated and the elevated UC emission is ascribed to a combined effect of enlarged particle size, improved energy transfer efficiency and changed local crystal field symmetry. More interestingly, it is proposed that the substitution pattern of Li+ ion in Lu2O3 host, in comparison with interstitial occupation, is more favorable for boosting UC emission by facilitating the energy transfer process and decreasing the local crystal field symmetry. This result is valuable for improving UC efficiency of lanthanide doped nanoparticles to fulfill the prerequisite of practical application.