Mandarin fish (Siniperca chuatsi) is one of the most economically important aquaculture species in China. Mandarin fish aquaculture has experienced major losses in the past few decades because of outbreaks of infectious spleen and kidney necrosis virus (ISKNV). Little is known about the immune mechanism of pathogenetic and resistant mandarin fish infected with ISKNV. Here, the transcriptome and proteome of the spleen of mandarin fish on the 8th day after ISKNV infection were analyzed using Illumina NovaSeq 6000 and isobaric tag for relative and absolute quantitation. Histology was observed by staining with hematoxylin and eosin. ISKNV loads were markedly higher in pathogenetic fish than in resistant fish. Serious tissue injury and inflammation were observed in the spleen tissue of pathogenetic fish. A total of 4667 and 3417 differentially expressed genes (DEGs), 258 and 54 differentially expressed proteins (DEPs), and 45 and 7 cor-DEGs-DEPs (i.e., correlation differentially expressed genes and proteins) were identified in pathogenetic fish and resistant fish, respectively. The DEGs were specifically enriched in the FcεRI signaling pathway in resistant fish; the up-regulated genes Rac (Rac1), FcεRIγ, TNFα, and IgE and the down-regulated genes 5-LO and SHIP might play a positive immune-regulatory role in anti-inflammation, resistance to pathogen infection, cytokine expression, and the generation of immune cells. In pathogenetic fish, DEGs and DEPs were specifically enriched in the natural killer cell-mediated cytotoxicity pathway, and the up-regulated genes Fyn and Shc might exacerbate tissue inflammation and inhibit NK cell-mediated cytotoxic pathways; the down-regulated protein perforin and up-regulated protein granzyme might inhibit the penetration of effector proteins and thus their ability to mediate the programmed cell death of ISKNV-infected target cells. The up-regulated cor-DEGs-DEPs BF, C8, and PLG were specifically enriched in the complement and coagulation cascade pathway, and the down-regulated cor-DEGs-DEPs p120ctn and MLC were specifically enriched in the leukocyte transepithelial migration pathway, which might inhibit complement cascade function, accelerate viral infection, and result in an excessive inflammatory effect. The findings of this study provide novel information relating to the molecular mechanism of pathogenicity and the resistance of mandarin fish infected with ISKNV.