Pre-weaning feeding is critical for calf growth, laying the foundation for future productivity and health. Nigella sativa seeds (NS) are rich in bioactive compounds with numerous beneficial effects on health and various pharmacological properties. This study aimed to investigate the supplementation of NS powder on performance, post-metabolic attributes, immunity, antioxidant capacity, and inflammatory responses in pre-weaning Friesian calves. Twenty-four Friesian male calves at 4 days of age with a similar genetic line, weighing 33.67 ± 0.6 kg, were randomly allocated to three groups (8 animals per group). The study comprised three groups: a control group (NS0) receiving no supplementation, and two experimental groups received either 1% (NS1) or 3% (NS3) NS supplementation for 84 days. All levels of NS supplementation significantly improved the final body weight and body weight gain in a linear manner (P<0.001), while the highest total dry matter intake was observed in NS1 group (quadratic; P<0.001). White blood cells (quadratic, P = 0.026), lymphocytes (quadratic, P=0.012), and monocytes (linear effect; P=0.001) significantly decreased, whereas red blood cells (linear; P=0.004), hematocrit (linear; P=0.002), mean corpuscular volume (MCV, linear; P=0.003), and mean corpuscular hemoglobin concentration (MCHC, quadratic, P=0.007), platelets (linear; P<0.001) increased in calves fed NS. Feeding calves diets supplemented with NS led to a significant linear decrease in plasma creatinine and liver enzymes (AST and ALT) compared to the control diet (P<0.01). Calves fed 3% of NS in their diets had lower plasma cholesterol (linear; P < 0.001) and triglyceride levels (linear; P=0.002) compared to calves in NS0 and NS1 groups. Polynomial analysis indicated a quadratic decrease in direct bilirubin (P=0.006), and a quadratic increase in immunoglobulin G (IgG, P=0.014) and M (IgM, P=0.032) in the calves fed the NS diet. All NS-supplemented groups showed a significant increase in IL-10 (linear; P<0.001), TAC (linear; P=0.006), and CAT (linear; P<0.001), and a significant decrease in IL-4 levels (linear; P<0.001) of the plasma of pre-weaning calves. As expected, pre-weaning calves fed diets containing NS (1% or 3%) exhibited a quadratic decrease in plasma malondialdehyde (MDA, P<0.001) levels compared to those fed diets without NS. Our findings suggest that incorporating up to 3% Nigella sativa into pre-weaning calf diets can enhance growth, bolster immune function, and mitigate oxidative stress, offering a promising strategy for improving health and sustainability on dairy farms.