Climate change significantly affects global and regional agriculture production thus food security. There are currently large areas suitable for maize production in the regions surrounding the Great Lakes (the Great Lakes region, GLR), one of the major maize production regions and economic engines in North America and the world. Will the GLR remain its high-yield under the future climate change? In this study, we use the climate change risk assessment platform CLIMADA to quantify the maize production associated risks over the GLR in the 2050s (2040-2069) and 2080s (2070-2099) under the Representative Concentration Pathways (RCP) scenarios RCP 2.6 and the RCP 6.0. The updated gridded global maize production, land use and the large ensemble of maize yield projections generated by the ISIMIP are used in this study. The results show that in the current maize production areas, the total loss could reach 7.143 million tons (MT)/year in the 2050s and 0.897 MT/year in the 2080s under the RCP 2.6; and even more losses are projected under the RCP 6.0, which could reach 8.472 MT/year in the 2050s and 20.571 MT/ in the 2080s. Based on current global maize price in US dollars, these losses could be $2.4 billion/year, $301 million/year, $2.83 billion/year and $6.91 billion/year, respectively. Maize production in most states and provinces in the Great Lakes region may drop by more than 7% by the end of this century under RCP 6.0. The production could drop more than 10% for some years or decades due to the additive effect of long-term warming and extreme annual and decadal climate variability. Sustained maize price increases and high price volatility could translate such risks to maize production into risks to food security and many other sectors of the local, regional and global economies. As the usage of maize continues to increase, the loss in maize production could continue resulting in more significant risks on food security and the economy. Our results also show a north-ward shift to higher latitudes in the maize growing areas, which implies that some of the current low-yield regions in the north could see a significant yield increase that may make up for some losses in the current high-yield areas in the south. Results from this study could provide guidance to various jurisdictions for their climate change adaptation/ mitigation practices.