Adverse effects from exposure to particulate matter <2.5 μm in diameter (PM2.5) on health-related outcomes have been found in a range of experimental and epidemiological studies. This study aimed to assess the significance, validity, and reliability of the relationship between long-term PM2.5 exposure and various health outcomes. The Embase, PubMed, Web of Science, CNKI, WANFANG, VIP, and SinoMed databases and reference lists of the retrieved review articles were searched to obtain meta-analysis and systematic reviews focusing on PM2.5-related outcomes as of August 31, 2021. Random-/fixed-effects models were applied to estimate summary effect size and 95% confidence intervals (CIs). The quality of included meta-analyses was evaluated based on the AMSTAR 2 tool. Small-study effect and excess significance bias studies were conducted to further assess the associations. Registered PROSPERO number: CRD42020200606. This included 24 articles involving 71 associations between PM2.5 exposure and the health outcomes. The evidence for the positive association of 10 μg/m3 increments of long-term exposure to PM2.5 and stroke incidence in Europe was convincing (effect size = 1.07, 95% CI: 1.05–1.10). There was evidence that was highly suggestive of a positive association between 10 μg/m3 increments of long-term exposure to PM2.5 and the following health-related outcomes: mortality of lung cancer (effect size = 1.11, 95% CI: 1.08–1.13) and Alzheimer's disease (effect size = 4.79, 95% CI: 2.79–8.21). There was highly suggestive evidence that chronic obstructive pulmonary disease risk is positively associated with higher long-term PM2.5 exposure versus lower long-term PM2.5 exposure (effect size = 2.32, 95% CI: 1.88–2.86). In conclusion, the positive association of long-term exposure to PM2.5 and stroke incidence in Europe was convincing. Given the validity of numerous associations of long-term exposure to PM2.5 and health-related outcomes is subject to biases, more robust evidence is urgently needed.