Install SO on an usb flash drive or hdd data?

Hi all,
I've discovered this fantastic world thanks to a PRI 3+ .. was looking for a better use of the pc board.
now i'm on RPI 3+, the OS is on the sd card, and an external hdd is used for data; as substitute of the RPI I'm planning to take a more performant intel nuc with 1 2,5"slot and 2 usb 3.0 ports; but I cant realize the best setting for so/data; should I install the SO on a flash drive and use the internal hdd for data? or I should partition the hdd for SO and data(with no external drives)?
I will use the NAS for serving some websites(nginx and mysql) and for smb, ftp and dlna; suggestions??
thanks all in advance

I have read several 3d but still I have not found an answer.
What would you do with 1 sata and 2 usb 3.0?
hdd over usb for stationary data + some small ssd over sata for OS(so I can trim) + usb flashdrive to store websites (only read and fast access time); would it work?