The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4–6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p= 0.007 **), miR-146a-5p (p= 0.036 *), miR-221-3p (p= 0.047 *), and miR-484 (p= 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p= 0.008 **), miR-143-3p (p= 0.009 **), miR-221-3p (p= 0.016 *), and miR-486-5p (p= 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p= 0.003 **) and miR-486-5p (p= 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.