This is actually quite easy to say. Just not as easy to do.
Things feel like busywork when the player is thinking of them as busywork. Which means that the following are probably going on for the player:
The gameplay is no longer interesting on a moment-by-moment basis. They've figured out the basic act of play and can essentially switch off higher brain functions during the main portions of your gameplay.
The elements of the story (assuming you have one) are not captivating the player's interest. From Mark Twain:
the author shall make the reader feel a deep interest in the personages of his tale and in their fate; and that he shall make the reader love the good people in the tale and hate the bad ones. Things like that. If the player flat out doesn't care, then you've failed as a storyteller.
So just make sure that your game is interesting to the player, either gameplay-wise or story-wise. Easy, right?
Keeping gameplay interesting for hours-long play times is exceedingly difficult. There's a reason why a lot of 20+ hour RPGs have a story and try to use that to maintain player interest. MMOs use a social component to keep people playing, but then they're not playing for your game, but for the other people in your game. It may as well be Monopoly at that point; it can still feel like work, just working to get something for someone else rather than themselves.
Sooner or later, players are going to figure out your game. The best way to handle this is to make sure that your core gameplay is flexible enough to keep throwing curves at the player that they are forced to react to. Make sure that there is no single optimal strategy. Change the gameplay as they play by introducing new mechanics and enemies that they have to react to in unexpected ways.
Most RPGs tend to be mechanically front-loaded. They show all of their basic play mechanics (magic systems, skills, etc) in the first few hours. They'll expand on the list of particular fields of mechanics (adding new spells and skills), but you generally don't get entirely new mechanics in the middle of a game. Getting new mechanics is a strong way of preserving interest.
Even something as simple as a mobility-based skill can radically change how the player plays and thus increase their interest in playing the game.
Use new enemies to help introduce new mechanics. Use those enemies to ensure that the player knows those mechanics exist and that the player can use them. And don't forget to test the player on all of their mechanics often, lest they fall out of habit with using them later.
While it's good to focus on the intellectual act of playing the game, don't discount the visceral or spectacle elements either. Hitting monsters with impressive-looking spells can hold a player's interests too. Probably not as much as interesting gameplay, but it is a way to help.
Story is a bit easier, in terms of basic structure. Especially since the elements of narrative is a fairly well-understood concept; there are many books and such on crafting a story. Really, start with Mark Twain's absolute vivisection of Fenimore Cooper's work and go from there.
Of course, this is a videogame, so you need to figure out how your story is going to work in terms of being a game. How will the player interact with the unfolding story.
One of the most difficult things to do in videogame storytelling (without stripping away all control from the player) is to maintain a strong element of pacing in the game's story.
For videogame storytelling, mysteries often work quite well. It's very difficult to tell story during gameplay, so games often have a lot of dead time between explicit narrative elements. As such, one way to maintain interest in the narrative is to build elements of mysteries and the unknown into the story. A few subtle hints can keep the player's interest by making them wonder what it all means during gameplay segments. A hint here, a suggestion there, and so forth.
Characters are also a good way to maintain player interest between plot points. Making the characters interesting, real, and deep, people that the player wants to get to know or wants to hate.
Sidequests are far too often just excuses to force the player to play through an area and lengthen the gameplay. That's fine if the gameplay is interesting on its own. But unless a sidequest's storyline has something to do with the story (whether it's a piece of a main plotline, some element of a more complex non-linear plot, or erudition about an important character, etc), the sidequest is going to feel pointless to the player.
Sidequests often detract from the pacing of the overall story. There's a reason why most novels and movies don't have characters going off on sidequests. It's hard to build tension if characters are distracted every 2 hours with something that's irrelevant.
TV shows and comics, long-form episodic stories, will often have the effective equivalent of sidequests: standalone episodes/issues that don't contribute to the main story. However, even if they don't contribute to a main plot, they often will contribute to character establishment/development or thematic progression.
Basically, make sidequests matter. Never add a sidequest for purely gameplay reasons. If story is going to matter for your game, then a sidequest needs to be justified by that story.