Objective: Root resorption, which results from orthodontic treatment, tooth fracture or inflammation, is a significant clinical concern as it contributes to tooth loss. However, the underlying mechanisms and pathophysiology of root resorption remain poorly understood. Orthodontically induced root resorption (OIRR) is thought to be triggered not only by mechanical compression of the periodontal ligament (PDL), but also by cellular responses within the PDL during the early phase of orthodontic force application (OFA). Recently, lithium (Li), a widely used medication for bipolar disorder, has shown potential in reducing OIRR. This study aimed to investigate the mechanisms by which Li suppresses OIRR, with a focus on PDL compression and the associated cellular responses. Materials and Methods: The maxillary first molars of 10-week-old male Wistar rats were moved for 14 days using a closed-coil spring. The rats were randomly divided to receive either lithium (Li; 0.64 mM/kg) or saline via daily intraperitoneal injection. PDL compression was measured using micro-CT on days 0, 3, 7, and 14, and compression ratios were calculated relative to day 0. Histological analyses evaluated OIRR, apoptotic cells, and odontoclasts. Results and Discussion: OIRR was significantly lower in the Li-treated group than the saline group. Although PDL compression ratios on day 3, but not on day 7, showed a strong correlation with OIRR severity in both groups, lithium reduced OIRR even in rats with similar compression levels. No significant difference in odontoclast numbers was observed between groups on day 3. While the number of apoptotic cells was positively correlated with PDL compression, it was significantly lower in the Li group. Li may reduce OIRR by attenuating excessive apoptosis induced by early PDL compression, rather than altering the mechanical compression itself. These findings suggest a novel biological mechanism by which Li mitigates root resorption during orthodontic treatment.