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<i>Silurus lanzhouensis</i> is a large endemic fish exclusively found in the middle and upper reaches of China’s Yellow River, with a restricted distribution range and a small population size and is listed as an endangered species. To investigate the potential genetic factors contributing to the observed decrease in the population of <i>S. lanzhouensis</i>, we have successfully assembled the first chromosome-level genome of <i>S. lanzhouensis</i>. This genome comprises a total of 30 chromosomes, with a size of 794.43 Mb, and 23,093 protein-coding genes. Comparative genomics analysis reveals that the genetic relationship between <i>S. lanzhouensis</i> and <i>S. meridionalis Chen</i> is the closest, and their common ancestor experienced two rounds of whole genome duplication (WGD) before diverging. Notably, amino acid metabolism-related pathways are enriched in the unique <i>S. lanzhouensis</i> gene family. In addition, we observed that the chemokine receptor and scavenger receptor gene families contracted in <i>S. lanzhouensis</i>, which may be associated with its diminished immune response. Our research findings provide valuable insights into the endangered mechanism of <i>S. lanzhouensis</i> and enhance our understanding of the evolution of Siluriformes fish.