Steel used for wind power must have high fatigue resistant properties because of its strict service conditions. The large-size (≥20 µm) CaO–MgO–Al2O3 (CMA) inclusions can lead to stress concentration and significantly reduce the service life. However, the occurrence of large-size inclusions is occasional and closely related to many factors, making it difficult to trace and control such inclusions. Herein, taking 42CrMo steel as the research object, we clarified the formation mechanism of CMA inclusions and determined its correlation with the steelmaking process. It was found that nearly all the large-size CMA inclusions in the bloom are located in the liquid region (<1873 K) of CaO–MgO–Al2O3 phase diagram. The results of inclusions automatic scanning showed that the low-melting-point CMA inclusions mainly form during VD treatment. Thermodynamic calculation revealed that the Al in molten steel reacts with CaO in slag under high vacuum condition, resulting in continuous diffusion of Ca from slag to steel. Then the dissolved Ca reacts with the existing solid or solid-liquid two-phase inclusions, leading to the increase of CaO in inclusions. The modified inclusions have good wettability with molten steel, and finally inherit to round bloom. Furthermore, the control policy to decrease the reaction extent between Al and CaO under vacuum condition was put forward in light of thermodynamic calculation. Under the same ratio of CaO/SiO2, with Al content increases, the corresponding Al2O3 content should be increased. Under the same Al2O3 content, with Al content increases, the ratio of CaO/SiO2 should be decreased.