The Seto Inland Sea region is a typical region for the development of modern Japanese manufacturing industry and the transformation of industrial structure. Based on the output value data of various industries in the Seto Inland Sea region from 1980 to 2019, this study uses industrial structure entropy and spatial dispersion index to explore the spatiotemporal evolution characteristics of the structure of the manufacturing industry in the Seto Inland Sea region, and analyzes the factors affecting its development. The study found that: ① The economic structure of the Seto Inland Sea region is complex and diversified, and the division of labor in the manufacturing industry is generally balanced, with differences between different prefectures; ② Nearly half of the industries in the manufacturing industry in the Seto Inland Sea region have significant industrial transfer phenomena, among which labor-intensive industries are mainly concentrated in coastal areas, and the overall structure shows a trend of spreading from coastal areas to surrounding areas. Capital-intensive industries are small in scale and more concentrated than labor-intensive industries. They are distributed in coastal prefectures. The concentration of technology-intensive industries is increasing, showing a trend of spreading from the eastern coastal areas of the Seto Inland Sea to the western areas; ③ From 1980 to 2019, the transportation machinery and equipment manufacturing, precision machinery and equipment manufacturing, general machinery and equipment manufacturing, food, beverage, feed and tobacco manufacturing industries in the Seto Inland Sea region of Japan showed a spatial diffusion trend, while the steel industry, textile industry, wood and wood products, ceramics and stone products, electrical equipment and machinery manufacturing and other industries showed a spatial agglomeration trend; ④ Natural resource endowments, technological innovation and talents, market demand, government policies, international environment and other factors have a promoting effect on the industrial layout of the manufacturing industry in the Seto Inland Sea region of Japan.