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Simple Summary: Kanglang white minnow (KWM, Anabarilius grahami), is a typical "3E" (Endangered, Endemic and Economic) fish species in Yunnan-Guizhou Plateau. As one of the traditional "Four Famous Fishes" in Yunnan province, it has become the major local aquaculture species with increasing demand after the success of artificial breeding. However, this economically important fish is highly susceptible to the infection of a parasite ciliate, Ichthyophthirius multifiliis (Ich), during the practical procedure of artificial breeding. To examine the host immune responses to Ich, we divided the experimental fishes into three groups (including control, early-infected stage, and late-infected stage) for transcriptome sequencing to analyze the differentially expressed genes (DEGs) and immune response mechanisms. The notorious parasite Ichthyophthirius multifiliis (Ich) has been recorded worldwide in fish species and causes white spot disease, posing major threats and resulting in severe losses to international fish production. Extensively effective strategies for treating Ich are not available yet, and genetic mechanisms of hosts in response to the parasite are still largely unknown. In this study, we selected Kanglang white minnow (KWM, Anabarilius grahami) to examine its liver transcriptional changes after Ich infection, as white spot disease is one bottleneck problem in exploring this economically important species. We divided the experimental fishes into three groups (control, early-infected, and late-infected) to examine differentially expressed genes (DEGs). A total of 831 DEGs were identified and classified into 128 significantly enriched GO (Gene Ontology) terms and 71 significantly enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Most of these terms or pathways were functionally enriched in immunity, inflammatory response, and apoptosis, such as nucleotide-binding oligomerization domain-like (NOD-like) receptor signaling, tumor necrosis factor (TNF) signaling, interleukin-17 (IL-17) signaling, and apoptosis pathways. We also identified 178 putative antimicrobial peptides (AMPs) and AMP precursors based on our previously reported genome assembly of KWM, and revealed that the expressional patterns varied according to different types. In summary, our work reported the first comprehensive transcriptional changes in KWM in response to the exogenous infection of Ich, which would lay a solid foundation for in-depth studies on disease defense or resistant strains selection in this valuable fish. [ABSTRACT FROM AUTHOR]