The common carp is an important aquaculture species that is worldwide distributed. Nowadays, intensive rearing in aquaculture increases the susceptibility of fish to various pathogens such as Aeromonas hydrophila, which has caused severe damage to carp production. However, systematic analysis on the host response of common carp against A. hydrophila is less studied. In order to better understand the common carp immune response process against bacteria at the global gene expression level, we examined transcriptional profiles of the common carp spleen at three timepoints following experimental infection with A. hydrophila. A total of 545 million 125-bp paired end reads were generated, and all trimmed clean reads were mapped onto the common carp whole genome sequence. Comparison of the transcriptomes between the treatment and control group fish revealed 2900 unigenes with significantly differential expression, including 732, 936, 928 genes up-regulated, and 248, 475, 700 genes down-regulated at 4 h, 12 h, 24 h post infection respectively. The captured significantly differentially expressed genes are mainly involved in the pathways including junction/adhesion, pathogen recognition, cell surface receptor signaling, and immune system process/defense response. Our study will provide fundamental information on molecular mechanism underlying the immune response of teleost against bacterial infection and might suggest strategies for selection of resistant strains of common carp in aquaculture.