A high amount of red meat consumption has been associated with higher risks of coronary heart disease (CHD) and all-cause mortality in a single food-exposure model. However, this model may overlook the potentially differential influence of red meat on these outcomes depending on the foods replaced by red meat. A PRISMA-compliant meta-analysis of prospective observational studies was performed to quantify the risks of CHD and all-cause mortality associated with the replacement of total, unprocessed, or processed red meat with fish/seafood, poultry, dairy, eggs, nuts, and legumes. The PubMed and Web of Science databases were searched to identify relevant articles published in any language from database inception to October 30, 2021. The prospective observational studies were considered relevant if they reported relative risks (RRs) and 95%CIs for the associations of interest. Thirteen articles were included. A random-effects model was used to estimate the summary RRs and 95%CIs for the associations of interest. Replacing total red meat with poultry (RR, 0.88, 95%CI, 0.82-0.96; I2 = 0%), dairy (RR, 0.90, 95%CI, 0.88-0.92; I2 = 0%), eggs (RR, 0.86, 95%CI, 0.79-0.94; I2 = 7.1%), nuts (RR, 0.84, 95%CI, 0.74-0.95; I2 = 66.8%), or legumes (RR, 0.84, 95%CI, 0.74-0.95; I2 = 7.3%) was associated with a lower risk of CHD, whereas substituting fish/seafood (RR, 0.91, 95%CI, 0.79-1.04; I2 = 69.5%) for total red meat was not associated with the risk of CHD. The replacement of total red meat with fish/seafood (RR, 0.92, 95%CI, 0.89-0.96; I2 = 86.9%), poultry (RR, 0.92, 95%CI, 0.90-0.95; I2 = 61.6%), eggs (RR, 0.91, 95%CI, 0.87-0.95; I2 = 33.8%), or nuts (RR, 0.92, 95%CI, 0.87-0.97; I2 = 81.9%) was associated with a lower risk of all-cause mortality, whereas the substitution of dairy (RR, 0.97, 95%CI, 0.93-1.01; I2 = 33.9%) or legumes (RR, 0.97, 95%CI, 0.93-1.01; I2 = 53.5%) for total red meat was not associated with the risk of all-cause mortality. Lower risks of CHD and all-cause mortality were more consistently observed for processed red meat replacements than for unprocessed red meat replacements. The results did not materially change when the analyses of total, processed, and unprocessed red meat were restricted to the studies that used a uniform substitution amount per unit of 1 serving/d. Keeping red meat, particularly processed red meat, consumption to a minimum along with increasing healthier alternative protein sources to replace red meat in the diet may contribute to the prevention of CHD and premature death. PROSPERO registration no. CRD42021259446.