This research was conducted to evaluate the effects of dietary supplementation with Artemia franciscana extract (AFE) on blood hematology, biochemical variables, antioxidant defense, adipokines, ovarian activity, reproductive performance, and ovarian and uterine integrities in rabbit does. A total of 120 female rabbits were fed diets fortified with 0 (AFE0), 100 (AFE1), 200 (AFE2), or 400 (AFE4) mg/kg of AFE. The HPLC analysis of AFE identified several main phenolic compounds, p-coumaric acid, caffeic acid, ferulic acid, catechol, syringic acid, gallic acid, and benzoic acid. The most prominent flavonoid identified in AFE was rutin, followed by quercetin, kaempferol, naringin, and catechin. Feeding rabbits with AFE resulted in a significant increase in red blood cell (RBC) and platelet counts (P < 0.01), while white blood cell (WBC) counts were significantly reduced (P < 0.05). Supplementation with AFE significantly enhanced circulating total protein and albumin levels and reduced the level of gamma glutamyl transferase (GGT, P < 0.01). Supplementation with 200 or 400 mg/kg AFE significantly elevated superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.05), with the AFE2 group exhibiting the highest (P < 0.05) levels of total antioxidant capacity (TAC), and glutathione peroxidase (GPx). Conversely, malondialdehyde (MDA) levels declined substantially across all treated groups (P < 0.01). The serum levels of adipokines, such as leptin and adiponectin, were significantly increased in all AFE-added groups (P < 0.01). All AFE-supplemented diets resulted in significantly higher serum levels of the reproductive hormones such as progesterone (PG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared to the AFE0 diet (P < 0.01). Dietary AFE supplementation significantly increased the number of corpora lutea, with the highest count observed in the AFE4 group, followed by the AFE1 and AFE2 groups (P < 0.01). AFE supplementation enhanced reproductive performance throughout the second and third parities, as evidenced by increased litter sizes and weights. Histological analysis revealed that AFE maintained the structural integrity of ovarian and uterine tissues. Furthermore, AFE administration significantly downregulated the immune-expression of Caspase-3 (P < 0.01). Overall, this study demonstrates that dietary supplementation with Artemia franciscana extract (AFE) at 200 or 400 mg/kg significantly modulates metabolic responses and enhances reproductive health in female rabbits. These benefits are driven by the regulation of adipokines and reproductive hormones, improved ovarian activity, and a strengthened antioxidant defense system.