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To explore whether a probiotic complex composed of <i>Lactobacillus rhamnosus</i>, <i>Lactobacillus plantarum</i>, and <i>Lactobacillus casei</i> can prevent or inhibit the inflammatory response caused by the invasion of <i>Plesiomonas shigelloides</i> in the southern catfish, we screened differentially expressed genes and enriched inflammation-related pathways among a control and three experimental groups and conducted analysis by transcriptome sequencing after a 21-day breeding experiment. Compared with those in the PS (<i>Plesiomonas shigelloides</i>) group, southern catfish in the L-PS (<i>Lactobacillus-Plesiomonas shigelloides</i>) group had no obvious haemorrhages or ulcerations. The results also showed that inflammation-related genes, such as <i>mmp9</i>, <i>cxcr4</i>, <i>nfkbia</i>, <i>socs3</i>, <i>il-8</i>, <i>pigr</i>, <i>tlr5</i>, and <i>tnfr1</i>, were significantly upregulated in the PS group compared with those in the L-PS groups. In addition, we verified six DEGs (<i>mmp9</i>, <i>cxcr4</i>, <i>nfkbia</i>, <i>socs3</i>, <i>rbp2</i>, and <i>calr</i>) and three proteins (CXCR4, NFKBIA, and CALR) by qRT-PCR and ELISA, respectively. Our results were consistent with the transcriptome data. Moreover, significantly downregulated genes (<i>p</i> < 0.05) were enriched in inflammation-related GO terms (lymphocyte chemotaxis and positive regulation of inflammatory response) and immune-related pathways (intestinal immune network for IgA production and IL-17 signalling pathway) in the L-PS vs. the PS group. Our results indicate that the infection of <i>P. shigelloides</i> can produce an inflammatory response, and probiotics could inhibit the inflammatory response caused by <i>P. shigelloides</i> to some extent.