This study was conducted to evaluate the effect of partial replacement of cotton seed meal in concentrate mixture by Nigella sativa (N. sativa) meal on nutrients digestibility, rumen fermentation, blood metabolites and performance of lambs. Eighteen of healthy Farafra male lambs aged between 5 and 6 months old and had average of 27.2 ± 1.3 kg body weights.  The lambs were randomly assigned into three groups, 6 animals each lasted for 90 days. The experimental groups were a control group (CON) fed basal diet containing concentrate mixture plus wheat straw and treated groups were fed basal diet plus 33.3% (T1) and 66.7% (T2 ) as a substitution of cottonseed meal by N. sativa in concentrate mixture. The lambs were fed 65% of their requirements as a concentrate mixture based on NRC guidelines and the rest were covered from wheat straw which given as roughages ad libitum. Three digestible trials were conducted with twelve mature local rams, distributed into three group and using three experimental diets, CON, T1 andT2.  In growth trail body weight were recorded and daily gain were calculated. Plasma metabolites, ALT, AST enzymes, thyroid hormones (T3 and T4) and total antioxidant capacity (TAC) were determined in blood samples. In digested trail rumen liquor samples were collected to measure the protozoal count, pH, ammonia N and total VFAs concentrations. Feed and fecal samples were analyzed using AOAC (2012). The results were statistically analyzed using of SPSS statistical package.  The results refer to the body weight and daily gain in T2 group was increased as compared with T1 and CON groups. The total DM and CP intake were higher (P<0.05) in T2 group as compared with CON group. The partially substitution of cotton seed meal by N. sativa meal  increased (P<0.05)  the concentrations of NH3-N and total VFAs, while the total protozoal count in rumen fluids  was decreased (P < 0.05)  as compared with CON group. Also, the plasma cholesterol and ALT enzyme was decreased (P< 0.05) in N. sativa meal groups compared to control group. However, T3 hormone and total antioxidant capacity (TAC) were higher (P<0.05) in N. sativa groups than control group. The nutrient digestibility was increased (P < 0.05) with increasing substitution rate from 33.3 to 66.7% of cotton seed meal by N. sativa meal. It can be concluded that the partial replacement of cottonseed meal in concentrate mixture by N. sativa can be used as an unconventional protein source in lambs' rations with no any harmful effect on performance of growing lambs..