Provided are an endoscope system, a processor device, and a method of operating an endoscope system that can easily capture a lesion and can display and observe a specific range. An endoscope system 10 includes an image acquisition unit 54 that acquires an endoscope image, a monitor 18 that displays at least a portion of the endoscope image, a region-of-interest detection unit 82 that detects a region of interest 124 at least in a non-display region 121 out of a display region 115 to be displayed on the monitor 18, and the non-display region 121 that is a portion excluding the display region 115, a guidance information generation unit 83 that generates guidance information to the region of interest 124 present in the non-display region 121 in a case where the region-of-interest detection unit 82 has detected the region of interest 124 in the non-display region 121, and a display control unit 66 that displays the guidance information on the monitor 18 in addition to the endoscope image.
