To evaluate CAD/CAM milling vibrations related to zirconia disk design, framework, and location of digital crown nesting during zirconia soft milling. In the present in vitro study, 25 round zirconia disks of 98 mm (R group) and 15 D-shaped zirconia disks of 71 mm (D group) were placed in a 5-axis CAD/CAM milling unit. The R group had 3 crown milling sites (n = 75) and the D group had 2 crown milling sites (n = 30). In the R group, site A was located 57 mm, site B was 92 mm, and site C was 123 mm from the machine holder attachment. In the D group, site A was 57 mm and site C was 123 mm from the machine holder attachment. A vibration meter (VB-8200; Lutron) was connected to the disk holder, and data (mm/second) were collected during the milling process at the different nesting locations. One-way ANOVA with post-hoc tests and Bonferroni correction for multiple tests were used to compare the groups (α = 0.05). In the R group, site C exhibited the highest mean vibration values compared with site A (P = 0.001). The first and second cutting tools (2.5 and 1 mm) exhibited statistically significant differences between the D and R groups at milling sites A and C (P < 0.001 and P = 0.003, respectively). Milling vibration increased as the distance between the machine holder arm and a digitally nested site increased. Round zirconia disks induced higher vibration values compared with D-shaped disks.