BACKGROUND: A large body of scientific evidence has established the impact of increased temperatures on human health. There is a relationship between extreme heat (either incremental temperature increase or heatwaves), and heat-related illnesses. This study aimed to collate the research findings on the effects of extreme heat on heat-related illness in a systematic review and meta-analysis, and to provide robust evidence for needed public health intervention. METHODS: We conducted a search of peer-reviewed articles in three electronic databases (PubMed, EMBASE, and SCOPUS), from database inception until January 2022. A random-effects meta-analysis model was used to calculate the pooled relative risks (RRs) of the association between high temperature and heat-related illness outcomes. A narrative synthesis was also performed for studies analysing heatwave effects. Assessment of evidence was performed in three parts: individual study risk of bias; quality of evidence across studies; and overall strength of evidence. RESULTS: A total of 62 studies meeting the eligibility criteria were included in the review, of which 30 were qualified to be included in the meta-analysis. The pooled results showed that for every 1 °C increase in temperature, when measured from study-specific baseline temperatures, direct heat illness morbidity and mortality increased by 18 % (RR 1.18, 95%CI: 1.16-1.19) and 35 % (RR 1.35, 95%CI: 1.29-1.41), respectively. For morbidity, the greatest increase was for direct heat illness (RR 1.45, 95%CI: 1.38-1.53), compared to dehydration (RR 1.02, 95%CI: 1.02-1.03). There was higher risk for people aged >65 years (RR 1.25; 95 % CI: 1.20-1.30), and those living in subtropical climates (RR 1.25; 95 % CI: 1.21-1.29). CONCLUSION: Increased temperature leads to higher burden of disease from heat-related illness. Preventative efforts should be made to reduce heat-related illness during hot weather, targeting on the most vulnerable populations. This is especially important in the context of climate change.