Final answer:
Stephen Douglas's major mistake in proposing the Kansas-Nebraska Act was underestimating Northern opposition to the spread of slavery, leading to significant political upheavals and contributing to the tensions that would eventually lead to the Civil War.
Step-by-step explanation:
One of Stephen Douglas's mistakes when proposing the Kansas-Nebraska Act was D. Underestimating the depth of Northern opposition to the spread of slavery. Douglas believed his proposal would support the Democratic Party and boost his presidential prospects by allowing the territories of Kansas and Nebraska to decide on slavery through popular sovereignty, which would essentially open these territories to slavery against the former Missouri Compromise stance.
The Kansas-Nebraska Act was assumed to make Nebraska a free territory due to its unsuitable climate for plantation slavery. Kansas, however, was contestable, and the act led to a violent struggle as pro-slavery and anti-slavery factions vied to control the state constitution. The act severely damaged the Democratic Party's strength in the North and contributed to the collapse of the Whig Party, marking it as an event that propelled the nation toward civil war.