Being 'in combat' is a bizarre and ridiculous thing. When playing tabletop RPGs like Dungeons and Dragons there is usually a sense of combat time in which characters take turns doing things on a short time scale. People act sequentially, which is ridiculous from a realism standpoint, but is the only practical way to have tactical combat in this sort of scenario. It leads to all kinds of weird things - for example, two characters can't walk down a hallway together. One has to go first, then the other when it is their turn.
Outside this silly (but necessary for our purposes) framework things flow much more naturally in a state I call narrative time. People can do things simultaneously and even perform activities that don't fit into discrete six second chunks. You could, for example, give a speech without having to check if every person in the room passes their turn!
The other day Naked Man asked me a rules question that touches on this strange construction. He wanted to know how to rule it if a player was readying a spell over multiple turns. If they say "I shoot a Magic Missile at any enemy that walks around that corner" and nobody walks around the corner by their next turn is the spell lost? Can they just choose to continue readying it? Can they keep the spell and do something else? Finally, if they can do all these things, can the players just wander through the dungeon constantly declaring that they are readying spells to attack at all times so the instant they see an enemy they unleash a barrage of magic?
I know what my GMs in highschool games would have done to anyone who tried to ready spells for extended periods like that. They would have said "oh, rocks fall, you die" and then waited for the player to stop being an ass. Or they might have had low level spellcasters cast illusions of monsters that walked around corners so the players unleashed fusillades of spells at an illusory beholder.
However, if I want to answer the question of how to handle this in general for a wide swath of players I think I would like to be a bit more thorough and within the rules.
I would definitely allow players to continue to ready a spell against a particular circumstance should it not arise. If you ready a Magic Missile against an enemy coming around a corner and nobody does, I would say you can just abandon that and do something else next round without losing the spell.
But as soon as anybody says they are readying a Magic Missile during their entire walk through the dungeon, well now that is a different thing. Readying a spell is a combat action. It makes no fucking sense outside of the combat time construct, so any time the players are operating in narrative time rather than combat time I would forbid combat actions completely.
If a player said "I am keeping a special watch on that well in the corner in case anything crawls out of it to attack us" I would absolutely take that into consideration and perhaps give them a bonus on a surprise roll or a roll to notice the monster leaping out of the well. Could even just decide that if a monster does come out they are definitely not surprised. What I definitely wouldn't do is let them ready a Magic Missile against that eventuality, because they are in narrative time until combat starts.
And since I am the GM in this case, *I* decide when we are in combat time vs. narrative time.
That is kind of a ridiculous solution, but I think it is the only one consistent with the rules of the game. Combat time is silly but it is an intrinsic part of DnD and you should make use of it when it is helpful, and keeping players from doing silly things with combat actions all the time is exactly the sort of place where you want to enforce the strict duality of game state.
My solution has the nice benefit of feeling elegant (once you accept the combat time construct) and also keeping people from doing abusive things. Readying spells and then not using them in combat isn't powerful, so there is no need to try to quash it. After all, you missed an entire turn and did nothing! All we need to do is prevent players from doing dumb stuff like trying to ready actions for hours on end, and combat vs. narrative time solves that neatly.