What specific version of MC are you running? MC26.0.98? There was a recent tweak for Media Keys when running MC in Media Server mode.
I press Fn to access the traditional F-Keys
By Media Keys, we are talking about Stop, Play, Pause, Next, Previous, Volume Up, Volume Down and Mute aren't we?
I think how well, or even if, Media Keys work on PCs depends a lot on the hardware (including but not limited to motherboard, BIOS, onboard or separate Sound Card, etc.), drivers, and software on that particular PC.
For example, my Workstation uses a Logitech G15 wired keyboard which has separate physical Media Keys. Setpoint is running. With Media Keys set to "Hot Keys" in MC all keys work, including Volume Up and Down, which controls the MC Internal Volume, while the System volume is set to maximum during playback by my device audio settings. These keys even work in Media Server mode, as I have "Translate hot keys when running as Media Server" checked.
They work even if MC isn't in focus, even when I'm not running Media Server on my Workstation.
However, I use a Logitech K400r wireless keyboard, on which the top row of keys are primarily Media Keys, with my HTPC and with basically the same settings there, the Volume Up and Down still control the System Volume, and not the MC Internal Volume. Setpoint isn't running on the HTPC and it just crashes if I try to run it, as is common with Setpoint. I probably should try to fix that, but I don't need to, because on my HTPC I control volume using my IR Remote controlling the AVR volume knob.
So I think you have to try different combinations of settings, and work out what works best for you, and in your environment. Try all the Media Key mode options, and see what each does. Internal Volume is still the best choice in MC, but for some people System Volume works better if they want to use Media Keys on a keyboard.
You could try running Media Server with MC, and see if the Media Keys then work when MC isn't in focus. Just turn on "Translate hot keys when running as Media Server".
You might also want to dig around in the Setpoint software and see if there are any settings in there that change behaviour. Update Setpoint to the latest, or find the best for your hardware.
Trial and error is the only way to really get Media Keys to work as you wish.