Aim: Cytokines are crucial low-molecular-weight proteins involved in immune responses. This systematic review highlights the need for in-depth studies on cytokines’ biological mechanisms, providing insights into disease onset and potential therapeutic strategies. Materials and methods: A comprehensive literature search identified 18 relevant articles, emphasizing the multifaceted role of cytokines in orthodontic treatment (OT). The quality assessment using the ROBINS-I tool ensures a rigorous evaluation of the included studies, contributing to the overall reliability of the findings. Results and Conclusions: This systematic review explores the intricate relationship between cytokines and OT. Cytokines exhibit different properties, influencing cellular activities through autocrine, paracrine, and endocrine activities. OT, aimed at achieving stable occlusion, induces tension and compression in the periodontal ligament (PDL), triggering cytokine release. Proinflammatory cytokines play a role in inflammation, influencing bone and soft tissue metabolism. Studies show elevated cytokine levels in gingival crevicular fluid (GCF) after orthodontic force application. The choice of orthodontic devices, such as self-ligating brackets, influences cytokine concentrations, indicating the importance of attachment design. Further research promises to enhance orthodontic practices, and optimize patient care.