Marine Isotope Stage 3 ( MIS 3) is a critical transition period between the relatively colder MIS 4 and Last Glacial Maximum (LGM) climate. It is marked by more pronounced seasonality and reduced greenhouse gases (GHGs) than the pre-industrial (PI) period, as well as by the presence of the Laurentide ice sheet (LIS) and Cordilleran ice sheet (CIS). This project performs simulations under pre-industrial and two different MIS 3 regimes (57.5 ka and 45 ka BP, where ka BP represents thousand years before present) using maximal and minimal ice sheet scenario of each selected time slices of MIS 3 regimes with AWI-ESM-2.1 (Alfred Wegener Institute–Earth System Model), a state-of-the-art climate model with unstructured mesh and low resolution, to examine the sensitivity of the simulated Atlantic meridional overturning circulation (AMOC) to MIS 3 insolation, GHGs, topography (including properties of the ice sheet) and examine the characteristics of the simulated large-scale atmosphere and ocean circulation, precipitation, ocean hydrography, sea ice distribution, and internal variability of MIS 3-maximal relative to those of in MIS 3-minimal ice sheet scenario. In the simulations with MIS 3 (maximal and minimal ice sheet scenario), Earth orbital parameters and GHGs forcing conditions applied, the AWI-ESM-2.1 simulation shows a JJA (June– July–August) warming and DJF (December–January–February) cooling over the mid and high latitudes and more precipitation in Intertropical Convergence Zone (ITCZ) are observed compared with minimal conditions. The simulated 57.5 ka BP (45 ka BP)- maximal global mean value, near-surface air temperature is ~1.14 °C (~2.31 °C) and sea surface temperature is ~0.36 °C (~1.36 °C) cooler, and more precipitation by ~0.36 mm/month (~3.81 mm/month) than the 57.5 ka BP (45 ka BP)-minimal, respectively. The presence of the LIS and CIS lead to an additional regional cooling over the Northern Hemisphere. The AMOC is deeper and intensified in maximal than minimal scenario. There is a decrease in the volume of Antarctic Bottom Water (AABW) reaching the Atlantic. At the same time, there is an increase in ventilation of the Southern Ocean, associated with a significant expansion of Antarctic sea ice and concomitant intensified brine rejection, invigorating ocean convection. The global mean value, 57.5 ka BP (45 ka BP)-maximal sea ice concentration is ~1.6% (~3.1%) thicker than the 57.5 ka BP (45 ka BP)-minimal, respectively with an expansion of sea ice in the Nordic Seas during boreal winter (March) and summer (September), causes more saline water over these regions due to brine rejection while forming sea ice. In conclusion, I find that the simulations capture spatially heterogeneous responses of MIS 3 climate.