This study aimed to compare the C-reactive protein level and visual analog scale scores of piezo- and rotatory-based surgical extraction of the third molar. As a split-mouth study, the comparative groups consisted of 25 patients, each of whom underwent surgical removal of the third molar by piezo on one side and rotatory bur on the other side. C-reactive protein levels were quantitatively assessed (enzyme-linked immunosorbent assay) before and immediately post-extraction. The immediate postoperative blood sample (baseline) C-reactive protein levels were compared with 24 h and 72 h post-op samples, both within and between the groups. Pain was assessed using the visual analog scale at 24 h and 72 h post-operatively. The C-reactive protein levels were lower in the piezo group than in the rotatory group, although the difference was not significant (p > 0.05). The visual analog scale score was significantly (p < 0.01) lower in the piezo group than in the rotatory group. The C-reactive protein levels increased in both the rotary and piezo groups from the pre-op to the immediate post-op value, but in the piezo group, the levels dropped back after 24 h. On the contrary, in the rotatory group, the C-reactive level kept increasing until 24 h; the visual analog scale score dropped significantly from 24 to 72 h for both the rotatory and piezo groups. Surgical techniques that could spare the surrounding soft tissues, such as the piezo, could aid in reducing overall postoperative morbidity.