Elevated levels of plasma homocysteine (Hcy) appear to be associated with a higher risk of occlusive vascular disease as well as a number of other clinical conditions. The exact mechanism involved is not fully understood. Recently, it has been shown that Thymoquinone, the most active component in Nigella Sativa (NiSa) seeds, as well as the seeds oil, caused almost complete protection against methionine-induced hyperhomocysteinemia (HHcy) in the plasma of rats as well as the oxidative stress associated with this state. Here Hcy levels in blood serum of rats fed a methionine-enriched diet (with deficient levels of folate, vitamins B6 and B12) for 7 weeks together with NiSa (at 250 mg/kg/day; oral suspension) led to 72.1 ± 3.35% protection against HHcy induced by the same diet without the seeds. There was no significant change in Hcy levels in control groups fed a standard diet with or without the seeds. Furthermore, the seeds imparted a 90.0 ± 4.0% protection against the rise in liver Hcy levels, and reduced the control levels by 28.0% ± 0.4%. The degree of protection in brain tissue homogenates reached a level of 29.0 ± 2.0%. In addition, there was no significant rise in Hcy levels in heart tissue under the excess methionine conditions, nor was there any significant effect by the NiSa on the levels on heart tissue Hcy under these conditions. NiSa treatment, however, significantly reduced the levels of Hcy in the control heart tissue by 43 ± 8%. On the other hand, the NiSa provided full protection against the rise in serum triglyceride levels (approx 3.0 fold) as well as the drop (24.2 ± 1.5%) in serum Superoxide Dismutase (SOD) antioxidant enzyme activity without causing any significant effect against the decrease in the total antioxidant status under the excess methionine conditions used. These results demonstrate the effective protection by NiSa against induced HHcy in serum, liver, and brain tissues together with its ability to reduce Hcy level in heart tissue.