thats tough just due to the amount of ground that covers. the gameboy, GBA, the DS and 3DS, and the PSP and Vita.
but if i had to definitively pick a 'best handheld game ever' it would have to be Pokemon Mystery Dungeon: Explorers of Sky. this game just has everything. an amazing story, a good soundtrack, a treasure trove of post game content, and the only dungeon crawler mechanics that i have ever been able to get into.