The purpose of the present study was to examine the effects of regular exercise on the abundance of targeted circulating microRNAs (miRNAs). The present analysis examined 20 previously sedentary adults from the HERITAGE Family Study who completed 20 weeks of endurance exercise training. The expression of 53 miRNAs related to cardiovascular disease were measured in serum collected at baseline and post-training by performing RT-qPCR on the Human Cardiovascular Disease miRNA array (Qiagen, Germany). The effect of regular exercise on circulating miRNAs was assessed using paired t-tests of baseline and post-training expression levels. A false discovery rate threshold of 5% was used to determine significance. Regular exercise resulted in significantly decreased mean serum expression of nine miRNAs (miR-486-5p, let-7b-5p, miR-29c-3p, let-7e-5p, miR-93-5p, miR-7-5p, miR-25-3p, miR-92a-3p, and miR-29b-3p; fold change range: 0.64-83, p = 0.0002-0.01) and increased mean expression of five miRNAs (miR-142-3p, miR-221-3p, miR-126-3p, miR-146a-5p, and miR-27b-3p; fold change range: 1.41-3.60, p = 0.001-0.006). Enrichment analysis found that these 14 miRNAs target genes related to over 345 different biological pathways. These results provide further evidence of the effects of regular exercise on the circulating miRNA profile.