Sickle cell anemia (SCA) is an autosomal recessive Mendelian trait characterized by symptoms that include acute and chronic pain, chest syndrome, pulmonary hypertension, stroke, kidney disease, and vaso-occlusive crises (VOCs), all of which worsen with age; VOCs are the leading cause of hospitalization and premature death in SCA patients. Currently, despite the existence of treatments for SCA, the negative consequences of VOCs' chronic inflammatory state demand the exploration of alternative methods of control. For this reason, the goal of this research was to find novel pathways and promising bioactive polyphenols for the treatment of SCA using a combination of network pharmacology and in silico approaches; due to polyphenols, they have shown widely reported anti-inflammatory properties. Initially, hub genes associated with inflammatory processes in SCA were identified by extracting differentially expressed genes (DEGs) from a publicly available GEO dataset (GSE53441), followed by their validation through system biology analysis, Polyphenols with anti-inflammatory activity were selected from natural product databases; finally, molecular docking and dynamics were performed with the polyphenols and the key protein derived from the selected hub genes. As a result, 10 genes associated with the Type I interferon (IFN-I) pathway in SCA were identified (MX1, FIT1, IFIT3, STAT1, ISG15, GBP1, OAS1, OAS2, OAS3, and RSAD); among them, STAT1 was selected as a central hub gene by regulating the expression of the rest. Docking and dynamics studies showed good binding energies among STAT1 and the fifteen polyphenolic extracted compounds, with quercetin, diosmetin, and fisetin showing the lowest binding energies. Identified flavonoids have been described in the past as compounds having anti-inflammatory and antioxidant features, as well as possible alternatives for SCA treatment.