The Hiruzen who fought Orochimaru loses with low-mid difficulty. Old Hiruzen with Edo feats loses with mid-high difficulty. Edo Hiruzen beats her with mid-high difficulty.
RDS still kills Hiruzen too if he can finish it but that's not going to happen when he was barely able to hold Orochimaru who is physically weaker than Tsunade. She can also summon the slug anytime who melts Hiruzen while he is trying to take her soul.
Not sure how much knowledge Hiruzen has on Tsunade. If he has his Edo feats, and if manga knowledge means he knows about Byakugo / regeneration, he should take it. He can make a clone or two and nail her with Raiton streams, paralyzing her, and then smash her skull in with his staff. If he doesn't know about regeneration, he may end up letting his guard down and getting pot-shotted.
it'll take a few, gradually adjusted, sequences of enma/shuriken/bomb-tags to create an opening for a direct hit w/ rai'ton/fuu'ton.
but it'll happen. 1 way is a double-delayed clone feint where a clone & hiruzen pressure Tsunade then cloning enma staff to imprison her when she counterstrikes; only a second or two is needed to prevent her shunshin & for hiruzen to get the free shot off.
he could also decimate her with a counter of his own by using a giant, fuu'ton/ka'ton-enhanced shuriken w/ a mass replication, finishing w/ enma staff.
Edo hiruzen wins low diff by makin 3~5 clones & performing a tactical blitz w/ nature transformation.