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Most cases of MND progress quite quickly, with noticeable decline occurring over the course of months. Although symptoms may present in one region, they will typically spread. If restricted to one side of the body they are more likely to progress to the same region on the other side of the body before progressing to a new region. After several years, most patients require help to carry out activities of daily living such as self care, feeding, and transportation.

MND is typically fatal within 2–5 years. Around 50% die within 14 months of diagnosis. The remaining 50% will not necessarily die within the next 14 months as the distribution is significantly skewed. As a rough estimate, 1 in 5 patients survive for 5 years, and 1 in 10 patients survive 10 years. Professor Stephen Hawking is a well-known example of a person with MND, and has lived for nearly 50 years with the disease. The television film Hawking starring Benedict Cumberbatch was made in 2004 about him and this disease.

Mortality normally results when control of the diaphragm is impaired and the ability to breathe is lost. One exception isPrimary Lateral Sclerosis (PLS), which may last for upwards of 25 years. Given the typical age of onset, this effectively leaves most PLS patients with a normal life span. PLS can progress to ALS, decades later.