The main quest has several parts, but many of them are simple fetch quests; only two require combat, and if you have been diligent about upgrading your ship and crew, neither should be especially difficult, though they may be tedious.
Eldacar's visit[edit]
After you amass enough experience (Level 7 appears to be sufficiently high), Count Eldacar, a representative from Waterdeep, will meet you at whatever port you have landed at to give you a quest: the Neogi, a race of spider-like slavers and one of the major antagonist factions of the Spelljammer setting, are acting with more coordination than usual, making them even more threatening. He promises treasure including a Major Spelljamming Helm if you succeed.
Clive's intelligence[edit]
There is no way to immediately make progress on this quest, so go back to your usual routine of running jobs. At some point, you will encounter a ship bearing a representative from Clive, the boss of Clive's Den on Garden, offering a thousand gold and asking for you to pay him a visit (to get the message, you need to head towards the ship and hail it, using the white flag icon, once it is sufficiently close).
Land at Clive's Den, and request an audience with Clive. He informs you that the Neogi are bad for business, and so he's decided to aid you. His plan is for you to obtain an artifact that will disguise the appearance of your ship, allowing you to fool the Neogi and learn more of their plans. The artifact (a sceptre) is located on an abandoned Dwarven Citadel that has been overrun by the undead. Clive will mark the location of the Citadel on your charts, allowing you to reach it via the Other Points of Interest option in the Navigation menu.
The Dwarven Citadel[edit]
The Citadel does not have weapons, so it's a simple matter to close and board it (using the grappling-hook icon). To obtain the sceptre, you must win a long fight against a large number of undead: around a half a dozen stacks of five skeletons, a similar number of zombie stacks, another half dozen or so revenants, and a single lich.
The fight is not especially dangerous, especially since the lich does not appear to have access to magic, but the fight is tedious and can go poorly if you are not prepared. In particular, the revenants and lich can only be damaged by spells and magic weapons, so ensure that you have memorized attack spells with all of your mages, and purchased at least one magical weapon for the strongest melee character in your crew (hopefully your captain). Strong armor, getting you to AC 0 or below, will mean that almost all of the enemies' attacks will miss, making the fight substantially easier. Finally, your clerics' turn undead ability will cause the zombies and skeletons to stop attacking, though it does not appear effective against the revenants or lich.
The area is large and can be confusing to navigate, so paying attention to where the enemies are located when it is their turn will make the fight go quicker. There are two major sections to the Citadel, linked by a teleporter (which appears as a raised square; simply order a character to walk onto the square to activate it). Once all the enemies are slain, the combat will end and you will receive the sceptre.
Spying on the Neogi[edit]
Return to Clive with the sceptre in hand, and he will tell you that he has received word of a Neogi rendezvous that you should infiltrate. Once again, this will be marked on your chart under Other Points of Interest. Simply go to the meeting point and meet/hail the ship; you will use the sceptre automatically to disguise yourself. You will get a message to go meet another ship to take part in a raid to obtain umber hulk slaves. Repeat the steps above to reach the new rendezvous point (as usual, the raid marker is in Other Points of Interest). Fortunately, you do not need to take part in the raid or in fact any combat, as the Neogi captain will beg for its life and reveal the location of the hidden mothership that's the cause of Realmspace's problems.
The final battle[edit]
Once you have made your final preparations, make your way to the mothership (as always, use Other Points of Interest to navigate to it). You will fight a few waves of battles -- first, four against Neogi deathspider ships, then one against a larger mindspider, then the final fight against the mothership itself.
The deathspider fights are not too challenging if you are properly upgraded (a galleon will all hull upgrades and at least eight weapons, ideally mostly heavy catapults, should be enough). They do not start out hostile, likely due to the sceptre, so one effective tactic can be to fly close enough to them that most of your weapons will hit in the initial volley, which should be enough to destroy the ship outright. If you do not have enough firepower to manage this, fighting at a medium distance will likely be better, since if the deathspider is able to return fire, it will be close enough to inflict significant damage.
The mindspider and mothership do start out hostile, and have sufficiently high hull values (100 for the mindspider, several hundred for the mothership) that this tactic will not work against them. An effective approach is to target their weapons via hit-and-run attacks, and chip through their hulls once they are defenseless. You can target weapons using the aiming icon -- simply select each of your weapons in turn and order it to target W for weapon, instead of the default H for hull (though be sure to switch back once you are ready to destroy the ships). Fire when your weapons are ready, then turn away from the enemy at full speed while you wait for them to reload. After a half-dozen or so volleys, you should have destroyed all the enemy's armaments, making them easy pickings.
Finale[edit]
Once you have destroyed the mothership, the endgame cinematic and credits will automatically play. You can continue playing after the endgame, though the reward is only about 10,000 gp, which might not even be enough to pay for repairs after the gauntlet you have just run. The promised Major Helm also does not materialize.