William Blake was a radical Romantic poet in the age of Reason, the late 18th-century England, challenging prevailing Enlightenment ideologies, especially Deism and Natural Religion. He was critical of prominent thinkers of his time, such as Bacon, Newton, and Locke, who formed the “Satanic Trinity” in his mind. In his works from his earliest writing like All Religions Are One to his final prophetic work, Jerusalem, Blake extensively criticized the scientific and experimental beliefs underlying Deism and Natural Religion. The idea of “The Poetic Genius” and “The True Man” formed a crucial basis for his art, redefining humanity. This study closely examines Blake’s critical content on Natural Religion in his writings and poetry, with a focus on his intense debates and discussions with figures like Bacon, Locke, and Newton. Furthermore, it explores the meanings of concepts like “Poetic Genius,” “Imagination,” and “The True Man,” shedding light on Blake’s vision of a restored humanity and the city of Jerusalem. Blake also argued that “Art and Science” must ultimately be united in the restored Eden called Jerusalem.