Taguchi’s method was applied to investigate the effect of main high energy ball milling (HEBM) parameters: milling time (MT), ball to powder weight ratio (BPWR), and milling speed (MS) on the CaCO3 crystallite size. The settings of HEBM parameters were determined by using the L9 (33) orthogonal experiments array (OA). The as-received and milled powders were characterized by X-ray diffraction (XRD) scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy. The crystallite size of CaCO3 varied between 140 and 540 nm depending on the HEBM conditions. The analysis of variance (ANOVA) was used to find the significance and percentage of contribution of each milling parameter. It was established that the MT is the most effective parameter followed by MS and BPWR. A confirmation test was carried out with a 90% confidence level to illustrate the effectiveness of the Taguchi optimization method. The optimum milling parameter combination was determined by using the analysis of signal-to-noise (S/N) ratio. Based on the S/N ratio analysis, optimal HEBM conditions were found MT 10 h, MS 600 revolutions per minute (rpm), BPWR 50:1.