An immune competence (IC) trait has been developed in livestock to combat infectious diseases through selective breeding. Here, we investigate whether circulating host-encoded microRNAs (miRNAs) are associated with immune responses to a commercial multivalent clostridial and leptospiral vaccine in Australian Angus steers, a proxy measure for IC. A total of 332 animals from 2 herds in New South Wales, Australia-Herd 1 (n = 168) and Herd 2 (n = 164)-were IC phenotyped on the day of yard weaning. Within a herd, animals were ranked by their antibody- (Ab-IR) and cell-mediated (Cell-IR) immune responses, and animals identified as "high" or "low" were in the top or bottom 7% of animals for each, respectively. A total of 47 steers that were identified as either low Cell-IR (n = 12), high Cell-IR (n = 11), low Ab-IR (n = 12), or high Ab-IR (n = 12) were selected for miRNA analysis. The IC score, a weighted average incorporating both Ab-IR and Cell-IR rankings, was calculated for selected steers. Our results indicate that the IC phenotype is associated with differences in circulating miRNA profiles. Linear regression modeling identified a potential association between pre-vaccination miR-150 levels and IC scores, while logistic regression modeling suggested that pre-vaccination miR-150 may differentiate IC high and low steers. Machine learning classification models further identified a 5-miRNA signature (miR-192, miR-150, miR-2285co, miR-155, and let-7a-5p) that classified high IC steers with 94% accuracy in this dataset. The findings of this pilot study suggest that circulating miRNAs warrant further investigation as potential predictors of immune response to vaccination and may provide insights into miRNA-regulated pathways involved in vaccine-induced immunity.