Not sure if this is possible, but its really annoying me that i cant find out how to. Is it possible to have a different set of controls for different ROMs/games on desmume?
no. use a launcher/frontend with capability for customizing per-game options. retroarch could do it. the way they'd implement it (and you could roll the same solution yourself) would be to swap ini files when launching desmume (or writing preferences to the ini file before launching desmume)