Background: Early recognition and management of symptoms can improve outcomes in cancer patients receiving treatment. A number of randomized trials have investigated the effects of adding proactive symptom monitoring to usual care (UC). These include web-based, application-based, or telephone-based assessments. Results have been variable, and the impact of proactive symptom monitoring on QoL, treatment toxicity and utilization of unscheduled acute care remains unclear. Methods: A systematic search of MEDLINE identified prospective, randomized trials that studied the effect of proactive monitoring and intervention versus UC in cancer patients receiving chemotherapy. The difference between proactive symptom monitoring and UC on the mean and SD for QoL using validated scales was collected for each study and pooled in a meta-analysis. Analysis was performed using the standardized mean difference (SMD) using random-effects modeling. The effect size was reported as the Hedges’ adjusted g. We also calculated the odds ratios (OR) for the occurrence of several common symptoms of any grade in the individual trials and pooled them in a meta-analysis. Statistical significance was defined as P < 0.05. Quantitative significance was defined as a difference in QoL score exceeding the minimal clinically important difference (MCID) based on previous studies for each QoL framework. Results: Of the 17 trials which met eligibility criteria, FACT-G and EORTC QLQ C30 were the most consistently utilized QoL tools. The mean difference in score between intervention and control at the last evaluation visits was 2.82 (95% CI -0.57 to 6.21; P = 0.10) in FACT-G and 2.33 (95% CI -0.29 to 4.96; P = 0.08) in EORTC QLQ C30, neither of which met quantitative or statistical significance. There was a statistically significant reduction in fatigue (OR 0.67, 95% CI 0.46 to 0.97; P = 0.04), but no difference in constipation (OR 0.63, 95% CI 0.34 to 1.17; P = 0.15), nausea (OR 1.03, 95% CI 0.72 to 1.47; P = 0.89), pain (OR 0.83, 95% CI 0.62 to 1.10; P = 0.19), or diarrhea (OR 1.41, 95% CI 0.40 to 5.01; P = 0.60). SMD for symptom severity was calculated for fatigue, diarrhea, and nausea. Severity of fatigue was statistically lower with proactive symptom monitoring (SMD -0.45, 95% CI -0.69 to -0.22; I² = 0%, P < 0.001), however, magnitude of effect was modest. Conclusions: Proactive symptom monitoring in cancer patients receiving treatment is not associated with significant or meaningful QoL improvement. Similarly, there is limited impact on individual toxicity.