Background: Findings from observational clinical studies examining the relationship between biomarker expression and theranosis in colorectal cancer (CRC) have been conflicting. Objective: We conducted this systematic review and meta-analysis to summarise the existing evidence to demonstrate the involvement of microRNAs (miRNAs) in chemoresistance and sensitivity in CRC through drug genetic pathways. Methods: Using PRISMA guidelines, we systematically searched PubMed and Science Direct for relevant studies that took place between 2012 and 2017. A random-effects model of meta-analysis was applied to evaluate the pooled effect size of hazard ratios (HRs) across the included studies. Cochran’s Q test and the I 2 statistic were used to detect heterogeneity. A funnel plot was used to assess potential publication bias. Results: Of the 4700 studies found, 39 studies comprising 2822 patients with CRC met the inclusion criteria. The included studies used one or a combination of 14 chemotherapy drugs, including 5-fluorouracil and oxaliplatin. Of the 60 miRNAs, 28 were associated with chemosensitivity, 20 with chemoresistance, and one with differential expression and radiosensitivity; ten miRNAs were not associated with any impact on chemotherapy. The results outline the importance of 34 drug–regulatory pathways of chemoresistance and sensitivity in CRC. The mean effect size was 0.689 (95% confidence interval 0.428–1.110), indicating that the expression of miRNAs decreased the likelihood of death by about 32%. Conclusion: Studies have consistently shown that multiple miRNAs could act as clinical predictors of chemoresistance and sensitivity. An inclusion of supplementary miRNA estimation in CRC routine practice needs to be considered to evaluate the efficacy of chemotherapy after confirming our findings with large-scale prospective cohort studies. PROSPERO registration number: CRD42017082196. © 2019, Springer Nature Switzerland AG.