An excessive amount of thyroid hormone is produced by an overactive thyroid gland, which keeps the body active. This study was carried out to investigate how hyperthyroidism-prompted liver damage and apoptosis could be alleviated with spirulina platensis and grape seed proanthocyanin extract in rats. Forty-eight male rats were divided into six groups. Group 1: received no drug. Group2 (hyperthyroidism): Rats received L-Thyroxine at dose of (50, 100, 200 ug/kg b.wt) orally for first three weeks of study, respectively. Group3 (GSPE Protected): Rats received GSPE (150/kg b. wt/day) for the first 3 weeks, then continued administered with L-Thyroxine for other 3 weeks. Group 4 (GSPE treated): Rats administered a daily dose of L-Thyroxinen for 3 weeks, followed by GPSE (150/kg b. wt/day) for another 3 weeks. Group 5 (Spirulina Protected); Rats received Spirulina and L-Thyroxine as in group III. Group 6 (Spirulina treated): Rats received Spirulina and L-Thyroxine similar to group IV. The data obtained demonstrated a substantial rise in serum T3 and T4 with marked decrease in TSH concentrations in hyperthyroid rats. A significant upregulation in miRNA 224 and downregulation in liver Protein kinase C alpha and miRNA 382 were observed in hyperthyroid rats. However, a significant decrease in T3, T4 and miRNA 224 with significant upregulation of miRNA 382 and PKCα and TSH level were observed after Spirulina and GPSE treatment and protection. In conclusion, GSPE and Spirulina platensis had a potential therapeutic and protective effect in Hyperthyroidism, through direct inactivation of T4 to T3 and mitigate micro-RNA and PKCα that essential for thyroid hormone homeostasis and thyroid functions.