The present experiment was carried out to study the influences of exogenously-applied nitric oxide (NO) donor sodium nitroprusside (SNP) and hydrogen peroxide (H2O2) as seed primers on growth and yield in relation with different physio-biochemical parameters, antioxidant activities, and osmolyte accumulation in wheat plants grown under control (100% field capacity) and water stress (60% field capacity) conditions. During soaking, the seeds were covered and kept in completely dark. Drought stress markedly reduced the plant growth, grain yield, leaf photosynthetic pigments, total phenolic content (TPC), total soluble proteins (TSP), leaf water potential (Ψw), leaf turgor potential (Ψp), osmotic potential (Ψs), and leaf relative water content (LRWC), while it increased the activities of enzymatic antioxidants and the accumulation of leaf ascorbic acid (AsA), proline (Pro), glycine betaine (GB), malondialdehyde (MDA), and H2O2. However, seed priming with SNP and H2O2 alone and in combination mitigated the deleterious effects of water stress on growth and yield by improving the Ψw, Ψs, Ψp, photosynthetic pigments, osmolytes accumulation (GB and Pro), TSP, and the antioxidative defense mechanism. Furthermore, the application of NO and H2O2 as seed primers also reduced the accumulation of H2O2 and MDA contents. The effectiveness was treatment-specific and the combined application was also found to be effective. The results revealed that exogenous application of NO and H2O2 was effective in increasing the tolerance of wheat plants under drought stress in terms of growth and grain yield by regulating plant–water relations, the antioxidative defense mechanism, and accumulation of osmolytes, and by reducing the membrane lipid peroxidation.