The encounter has two parts: a preparation (wake-up) phase where you poison the sleeping Duke, and the battle phase once he is awake.
Preparation phase — brewing poison. Duke starts asleep and must be weakened with arder-musca poison, made from arder powder, musca powder and salax salt gathered inside the asylum. Each poison needs six portions of each ingredient, and two poisons are required to wake him, so you need twelve of each ingredient in total. While gathering, you must avoid three hazards:
- Gas vents around the central salt piles release gas in a 3x3 area, draining 4 prayer points and dealing up to 12 damage (reducible with a slayer helmet or gas mask). The vents ignite in a predictable, looping pattern.
- Ice falls near the mushrooms randomly strike a tile, freezing you for 2 ticks and dealing up to 18 damage; a shadow looms over the target tile as a warning.
- Extremities periodically wake and unleash a gaze in a cone, starting from the middle, then south, then north on both sides; being caught freezes you for 5 ticks, drains a quarter of your prayer, and deals up to 70 damage. You can ignore them entirely by starting from one tile south of the southern extremity and running straight to the mushrooms, only watching for ice falls (and start one tile north of the northern extremity to do it in reverse).
The salt piles sit in the centre, surrounded by the gas vents; bringing the best pickaxe speeds up mining, and 80+ Mining means only two harvests are needed. The mushrooms are at the far ends past the extremities. In each corridor there are only two truly safe tiles — the tile you pick the mushrooms from and the tile beside it — which are never targeted by ice falls and are safe from the nearby extremity. Grind the mushrooms into powder (at 70 Herblore each mushroom gives five powder, so three of each type are needed; at 80+ Herblore only two of each), place twelve of each ingredient into both Fermentation Vats, let them ferment, then collect two poisons and feed them to Duke to wake him. With Herblore 62, 70 or 80 you can prepare enough poison for 2, 3 or 4 kills at a time, and mushrooms grow back after each kill, so you can stockpile many kills' worth with no downtime in between.
Battle phase. Awake, Duke has 485 Hitpoints and attacks on a five-tick cycle (3.0 seconds). Keep Protect from Melee on and stay in melee range:
- Icicles + slam (melee). In melee range he raises his arms, spiking icicles in a 3x3 (up to 11 damage, or 5 through Protect from Melee), then slams down for up to 56 damage without prayer (41 with). The slam always hits regardless of your bonuses.
- Blue projectile (magic). If you are outside melee range he launches a magical projectile for up to 48 damage, dealing significant damage even through Protect from Magic. This is why you always force melee.
- Freezing Gaze. Every fifth standard attack he opens the eye in his body (game message: "Duke Sucellus turns his gaze upon you..."). If you are not standing directly behind a pillar within 5 ticks, you take up to 101 damage, almost always a one-shot kill. Hide behind a pillar every time.
- Gas Flare. He spits gas toward the vent closest to you for up to 12 damage; move to the opposite pillar. Above 75% health he uses it every five attacks, four attacks above 25%, and three below 25%; below 50% health he launches two flares instead of one.
Enrage. At 25% health (121 HP), Duke speeds up from a 5-tick (3.0s) to a 4-tick (2.4s) cycle. With a 5-tick weapon you can only safely attack every other hit during enrage; a 4-tick weapon such as Emberlight or Arclight can match his speed. After he dies he stays down for a few seconds, drops his loot, then goes back to sleep.