There is growing evidence that substituting animal-based with plant-based foods is associated with a lower risk of cardiovascular diseases (CVD), type 2 diabetes (T2D), and all-cause mortality. Our aim was to summarize and evaluate the evidence for the substitution of any animal-based foods with plant-based foods on cardiometabolic health and all-cause mortality in a systematic review and meta-analysis. We systematically searched MEDLINE, Embase, and Web of Science to March 2023 for prospective studies investigating the substitution of animal-based with plant-based foods on CVD, T2D, and all-cause mortality. We calculated summary hazard ratios (SHRs) and 95% confidence intervals (95% CI) using random-effects meta-analyses. We assessed the certainty of evidence (CoE) using the GRADE approach. In total, 37 publications based on 24 cohorts were included. There was moderate CoE for a lower risk of CVD when substituting processed meat with nuts SHR (95% CI): 0.73 (0.59, 0.91), n = 8 cohorts, legumes 0.77 (0.68, 0.87), n = 8, and whole grains 0.64 (0.54, 0.75), n = 7, as well as eggs with nuts 0.83 (0.78, 0.89), n = 8 and butter with olive oil 0.96 (0.95, 0.98), n = 3. Furthermore, we found moderate CoE for an inverse association with T2D incidence when substituting red meat with whole grains/cereals 0.90 (0.84, 0.96), n = 6 and red meat or processed meat with nuts 0.92 (0.90, 0.94), n = 6 or 0.78 (0.69, 0.88), n = 6, as well as for replacing poultry with whole grains 0.87 (0.83, 0.90), n = 2 and eggs with nuts or whole grains 0.82 (0.79, 0.86), n = 2 or 0.79 (0.76, 0.83), n = 2. Moreover, replacing red meat for nuts 0.93 (0.91, 0.95), n = 9 and whole grains 0.96 (0.95, 0.98), n = 3, processed meat with nuts 0.79 (0.71, 0.88), n = 9 and legumes 0.91 (0.85, 0.98), n = 9, dairy with nuts 0.94 (0.91, 0.97), n = 3, and eggs with nuts 0.85 (0.82, 0.89), n = 8 and legumes 0.90 (0.89, 0.91), n = 7 was associated with a reduced risk of all-cause mortality. Our findings indicate that a shift from animal-based (e.g., red and processed meat, eggs, dairy, poultry, butter) to plant-based (e.g., nuts, legumes, whole grains, olive oil) foods is beneficially associated with cardiometabolic health and all-cause mortality.