Phosphate ore is an essential resource for producing phosphate fertilizer. International phosphate ore is overmined, and phosphorus resources are becoming depleted; improving the utilization efficiency of medium- and low-grade phosphate ore powder (PR) through activation is the key to the sustainable and efficient use of phosphorus resources. However, the traditional activation method is inefficient and has some limitations on the grade of phosphate ore. In this study, a combination of mechanical activation and low molecular weight organic acid activation was used to activate medium- and low-grade phosphate ore powders, and the activation effects of different mechanical activation conditions, such as mechanical grinding time, the addition of different types and proportions of active minerals (zeolite, bentonite, and kaolin), and different types of low molecular weight organic acids (oxalic acid, tartaric acid, malic acid, and citric acid), on phosphate ore powder were compared. The results show that mechanical activation had a synergistic effect with low molecular weight organic acid activation. Mechanical activation can reduce the particle size of phosphate ore powder and increase the release of effective phosphorus from phosphate ore powder. Mechanical activation for 60 min reduced phosphate ore powder's median diameter (D50) from 41.67 μm to 10.59 μm and increased the effective phosphorus leaching rate from 1.19% to 8.27%. The phosphorus release effect of low molecular weight organic acids was oxalic acid > tartaric acid > malic acid > citric acid, with the optimal concentrations of 0.1 mol/L, 0.3 mol/L, 0.5 mol/L, 0.2 mol/L, and the optimal activation cultivation times were all 6 days. This study optimizes the activation method of phosphorite powder, which can not only alleviate the current global shortage of phosphorite resources but also reduce environmental pollution while maximizing the use of phosphorite resources.