Fish health can be affected by many environmental factors including infection with pathogens. Infectious disease can lead to high mortality in wild populations and in aquaculture, resulting in significant economic losses. Teleost fishes share a highly conserved response to pathogen infections, starting with an immediate activation of the innate immune response before shifting to an adaptive immune response. Fishes also show altered transcriptomic expression in stress-related genes during acute and chronic infections. The ciliate Ichthyophthirius multifiliis ( Ich ) is one of the most widely distributed ectoparasites for freshwater fish, providing the possibility to identify infection severity via phenotypical assessments. Molecular markers are increasingly incorporated in health assessments and to determine sublethal physiological responses to stressors. We evaluated the effects of an infection with Ich using the pelagic fish species delta smelt ( Hypomesus transpacificus ) as a model. We investigated transcriptional changes of ten genes belonging to the innate immune response and five heat shock genes related to thermal and general stress response. Molecular assessments were conducted in three tissues (gill, spleen and kidney), and collected from fish with different infection intensities. The combination of molecular markers, including immune and stress-related genes, resulted in significant differentiation between infection levels in all tissue types. The strongest results were observed in gill and kidney, however, the detection of infection severity was most effective when combining the transcriptomic results from all tissues. Chemokine cxcb was the most responsive gene in all tissues and provided significant upregulation in fish with visible Ich -infection. The identification of molecular markers targeting fundamental host responses associated with infections is contributing to the establishment of techniques to assess fish health in natural habitats and in aquaculture.