Roderick Usher dies when his sister, Madeline, thought to have died shortly before, emerges from her grave, enters Roderick's room, and collapses on top of him. Both siblings die. It is not clear why Roderick buries Madeline alive in the first place, but it seems that she kills him to take revenge.

Although Roderick Usher is clearly very ill from the time of the narrator's arrival, it is not this illness that kills him. It is highly arguable, however, that the illness would eventually have killed him had his actual fate not befallen him.

Immediately upon his arrival, the narrator takes note of his childhood friend's diminished physical and mental state. Even before entering the house, the narrator feels a fearful and unwelcoming atmosphere about the building. Despite his misgivings, he enters the manor to find his friend looking gravely ill. Roderick explains that his illness is hereditary and that there is nothing that can be done for him.

An atmosphere of darkness and fear pervades the House of Usher right from the start, and this uncomfortable ambience grows stronger in the aftermath of Madeline's supposed death. Once she returns in her bloodied robes, taking Roderick's life in her final, vengeful act, the narrator runs for his life amid a storm and turns to see the House of Usher being swallowed.