If you take the Unbalanced Scale node for Smite (Smite also casts a lightning bolt at 3 nearby enemies) the lightning bolts can hit mobs off-screen, though it appears only if the mobs are towards the bottom left of the screen (red highlighted area below). I was running through a monolith & when the Imperial Spires were off-screen to the bottom left I noticed lightning bolts heading off-screen & then after a while the monolith said I’d destroyed the spires, despite me never having even seen them on-screen…
It seems to fire off-screen regardless of whether there are sufficient mobs to target on-screen but only towards the bottom left quadrant of the screen.
Edit: Apparently it can also target mobs off screen towards the top right as well, not just the bottom left, though it’s quite hard to get a pic.