although a lot of settings work without a reboot, it depends on the setting you actually change that might lead to a not responding web interface.
What might cause this error: Changes on WiFi / LAN page. If you change the IP-Address (to a fixed one) or change the Name of the Device (!) on the settings page, the URL of the Webinterface changes too.
Enabling WiFi and disconnect from LAN (Ethernet) might also be a problem, if your router needs some time to refresh its routes.
In all cases it might be helpful to look at the router and directly access the device by IP-Address.
Hope this helps,