In this work, the effects of temperature, acid concentration, and mechanical activation on dissolution of ilmenite were studied using the statistical design of experiment technique. Mechanical activation was carried out using a planetary ball mill in dry mode, and the resulting structural changes were characterized by the particle size analysis, specific surface area measurements, and X-ray diffraction method. The results obtained indicated that intensive milling led to a significant decrease in the ilmenite particle size and that after 20 minutes, particles tended to agglomerate. However, after 90 minutes, the BET specific surface area increased to 9.36 m2/g. In addition to surface changes, mechanical activation led to intense changes and disorders in the crystal structure of ilmenite as amorphization degree increased to 94.30% and the volume weighted crystallite size and lattice strain changed from 346 nm and 0.13% to 14 nm and 1.44%, respectively. The results of the dissolution tests in the form of experimental design indicated that a suitable model could fit the experimental data in 95% confidence level. The coefficient factors for acid concentration, mechanical activation, and temperature were 3.75%, 33.04%, and 9%, respectively. Mechanical activation had the highest effect on titanium extraction in comparison to the other factors involved. Also in addition to its dominant effect on ilmenite dissolution, it also weakened the temperature effect. However, the results of the kinetic tests proved that mechanical activation led to promotion of the temperature effect on increasing the dissolution reaction rate in the initial stages. Finally, a dissolution yield of more than 98% was achieved through 90 minutes of activation at 95° C and 55 wt.% acid concentration.