Cemented paste backfill (CPB), a technology placing the solid waste into mined-out stopes in the mine through pipeline transportation, has been widespread all over the world. The resistance loss is an important parameter for pipeline transport, which is significantly affected by the slurry characteristics. However, the coupling effect of inlet velocity (IV), particle mass concentration (PMC), and particle size (PS) has not been well evaluated and diagnosed. Hence, the CFD-based three-dimensional network simulation of CPB slurry flow in an L-shaped pipe at different combinations of the three parameters was developed using COMSOL Multiphysics software, and the findings were validated through a loop experiment. The results show that increasing IV and reducing PS will contribute to the homogeneity of the slurry in the pipeline, while the PMC presents little effect. The pipe resistance loss is positively correlated with IV and PMC and negatively correlated with PS. The sensitivity to the three parameters is IV > PS > PMC. In particular, the resistance loss is minimal at IV of 1.5 m/s, PMC of 72%, and PS of 1000 um. The calculation model of resistance loss regressed from simulation presented a high accuracy with an error of 8.1% compared with the test results. The findings would be important for the design of the CPB pipeline transportation and provide guidance in the selection of transfer slurry pumps, prepreparation of backfill slurry, and pipe blockage, which will improve the safety and economic level of a mine.