To explore long-term impact of organic and inorganic fertilizers on soil health and grain quality, we monitored the enzyme activities and chemical properties of soil; and chemical composition of grain from eight treatments at an experimental field site established in 1996. There were eight treatments applied to both wheat and maize seasons: a control; four inorganic fertilizers, that is, nitrogen and phosphorus (NP), nitrogen and potassium (NK), phosphorous and potassium (PK) and nitrogen, phosphorus and potassium (NPK); farm yard manure alone (FYM) and addition of FYM at two different doses (100 and 50% of recommendation) to NPK that is, NPK + FYM and ½ NPK + FYM. After 11 years of the experiment the NPK + FYM and ½ NPK + FYM treatments had the highest yields, about 5 Mg maize ha −1 and 2 Mg wheat ha −1 with about 2 and 0.5 Mg ha −1, respectively more than the NPK treatments. The dehydrogeanse activity of soils increased significantly in FYM and ½ NPK + FYM. Except urease all other enzymatic activities were increased in those treatments, which received manure. Urease activity was higher in mineral-N applied plots. Grain protein content of both maize and wheat was highest in mineral fertilized plots. Test weight also increased significantly on application of mineral fertilizer. Plots treated with half dose of recommended mineral fertilizer along with FYM were higher in urease, phosphomono and diesterase activities than that of NPK + FYM treated plots. Long-term application of inorganic nutrients along with FYM improved grain mineral composition and yield. Inhibition of few enzymatic activities were also observed upon application of inorganic nutrients either alone or in combination.