Amphibious buses are extensively used worldwide for transporting people to and from tourist attractions across water and land. Although numerous studies on self-driving technologies have been reported, research on the automatic operation and navigation of an amphibious vehicle has been sparse; moreover, owing to the size of the amphibious vehicles, automatic transport of multiple people is not possible. Therefore, in this study, we attempted to realize unmanned operation of a sightseeing amphibious bus for 45 passengers. The bus was outfitted with a by-wire system. On the vessel side, an actuator, similar to that used in JOY cars, was installed to turn the captain’s steering wheel. We also developed a software for the automatic operation and navigation of the bus. The relationship between the car’s steering-wheel angle and the front-tire angles is linear, whereas that between the captain’s steering-wheel angle and the vessel’s rudder-plate angle is not (and was approximated with a sixth-order polynomial). Furthermore, Autoware—a leading autonomous-driving software utilizing model-based predictive control algorithms to control the steering wheel of automobiles—was employed in this work. These algorithms were altered using Nomoto’s KT vessel model equation to improve the accuracy of vessel-path tracking. To the best of our knowledge, till date, no studies have documented the functioning of self-driving vessels using predictive controls based on Nomoto’s KT vessel model equation. In accordance with the vessel navigation rules based on the Autoware obstacle avoidance logic, LiDAR, cameras, and sonars were employed to detect obstructions and give-way paths. Thus, we successfully demonstrated the working of world's first self-driving amphibious bus, with automated controls for entering/exiting water and during give-way operations.