Circulating microRNAs (miRNAs) regulate inflammatory responses and have emerged as potential minimally invasive biomarkers of disease. However, comprehensive profiling of circulating miRNAs in naturally occurring inflammatory conditions in dogs remains limited. This study aimed to characterize circulating miRNA expression profiles using small RNA sequencing in plasma samples from dogs with pyometra, non-reproductive inflammatory diseases, and healthy controls to identify shared and disease-related miRNA alterations. Global expression patterns, including heatmap and principal component analysis (PCA), demonstrated separation between healthy controls and diseased dogs. Based on DESeq2 analysis (adjusted p-value < 0.05), 39 circulating miRNAs were commonly altered in both pyometra and non-reproductive inflammatory diseases compared with healthy controls. A total of 83 miRNAs were differentially expressed in the pyometra group, whereas 4 miRNAs were differentially expressed in the non-reproductive inflammatory disease group. Direct comparison between the two disease groups further identified three circulating miRNAs—cfa-miR-885, cfa-miR-599, and cfa-miR-122—as significantly differentially expressed. These findings suggest that circulating miRNA profiles in dogs with pyometra reflect both systemic inflammation and condition-related molecular variation. Further studies with larger cohorts are warranted to validate the clinical relevance of these candidate circulating miRNAs.