The aim of the study was to evaluate on the effectiveness of screening modalities in the prevention of colorectal cancer (CRC) occurrence and deaths. General meta-analysis was performed to produce pooled estimates of the effect of CRC incidence and mortality using a search of PubMed, Web of Science, and the Cochrane Library for eligible studies from January 1992 to March 2016. A network meta-analysis was performed to synthetically compare the effectiveness of 5 frequently used screening modalities. A total of 44 studies with a focus on mortality from CRC using different screening methods were included. General meta-analysis showed that fecal immunohistochemical testing (FIT), flexible sigmoidoscopy (FS), colonoscopy, combination of fecal occult blood testing and FS screening respectively reduced CRC mortality by 59% (relative risk [RR], 0.41; 95% confidence interval [CI], 0.29-0.59), 33% (RR, 0.67; 95% CI, 0.58-0.78), 61% (RR, 0.39; 95% CI, 0.31-0.50), 38% (RR, 0.62; 95% CI, 0.42-0.91) compared with no screening, whereas guaiac fecal occult blood testing (gFOBT) reduced CRC-related mortality by 14% (RR, 0.86; 95% CI, 0.82-0.90). Subgroup analysis showed that summary estimates of reduction in distal CRC mortality and proximal CRC mortality were 26% (95% CI, 62%-89%) and 10% (95% CI, 83%-98%). A network meta-analysis revealed rank probability analysis in which the colonoscopy had a 94.6% probability of being the most effective examination to reduce CRC mortality. In addition, the network meta-analysis estimated odds ratio, which was a 79% reduction (95% CI, 0.09-0.60) in CRC mortality when screening with FIT was compared with annual or biennial gFOBT and colonoscopy was approximately 80% more effective than gFOBT for reducing CRC mortality (RR, 0.25; 95% CI, 0.13-0.54). Analysis of the effects of different screening methods showed that there was a significant reduction in the incidence of colon cancer, excluding gFOBT. This meta-analysis confirmed that gFOBT, FIT, FS, and colonoscopy were all effective in preventing CRC deaths and a major reduction in distal but not proximal CRC mortality was found. In addition, they were more effective in preventing CRC incidence in addition to gFOBT. The network meta-analysis suggests that colonoscopy is the most effective screening for preventing CRC deaths.