Systemic sclerosis (SSc) is an autoimmune rheumatic disorder distinguished with fibrosis and vascular injury and structural alteration, coexisting with Reynaud’s phenomenon. The crosstalk between activated fibroblasts, immune effectors, and endothelial cells are the primary culprits in disease process. Fractalkine (FKN) or CX3CL1 is an unremarkable membrane-bound soluble chemokine and an adhesion molecule expressed on pro-inflammatory cytokine. In this systematic review, FKN and its receptor’s (CX3CR1) role in mediating inflammatory processes focusing on the pathogenesis of SSc is investigated. FKN is one of the most influential molecules which monitors the trafficking of inflammatory cells through the endothelium and has been observed to have pronounced expression in inflammation. The correlation between increased CX3CL1 levels in SSc and interstitial lung disease was established, and it was noted that CX3CL1 is predominantly co-localized with infiltrating mononuclear cells and epithelia within the lungs. The interstitial lung disease prediction and its progression may be available through augmented concentrations in SSc patients. Conclusively, Emerging evidence claims that FKN could be expressed in numerous tissues, taking part in the CX3CR1 positive cell accumulation at sites of inflammation and, as a result, involved in countless rheumatic diseases such as rheumatoid arthritis, Systemic lupus erythematosus, and scleroderma. Besides, it may play a prominent part in the SSc pathogenesis, involving vascular injury and tissue inflammation. Its estimation could be used as a serological marker for the recognition and follow-up of skin and pulmonary complications.