Edwardsiella tarda is an important Gram-negative bacterium that causes systemic infections in a wide range of hosts including fish. The pathogenic mechanisms in this disease are still poorly understood in fish. Indian major carp, Labeo rohita were intraperitoneally challenged with a pathogenic isolate of E. tarda to measure sequential changes in immunity level. A significant decrease in the superoxide production, myeloperoxidase, alternative complement activity, total protein levels and antiprotease activity of serum was marked in the infected fish. However, the serum lysozyme activity and haemagglutination titre were raised in the infected fish. Similarly, a significant rise in specific antibody titre was noticed on and after 10 days post-challenge. This study also elucidates the changes in the relative expression of some immune-related genes viz., interleukin 1-beta (IL-1β), inducible nitric oxide synthase (iNOS), complement component C3, β 2-microglobulin, CXCa, tumor necrosis factor-alpha (TNFα), and C-type and G-type lysozymes during the infection. Significant up-regulation of IL-1β, iNOS, C3, CXCa and expression of both types of lysozyme genes was noticed at 6–12 h post-challenge (h.p.c.) whereas down-regulation of β 2-microglobulin and TNFα genes was observed after 48 h p.c. The results obtained here strengthen the understanding on molecular pathogenesis of edwardsiellosis in L. rohita.