I suppose you could always Gate in a Zaratan or Elder Tempest.  That ought to do it.

Gate into a stream of lava/magma from the Elemental Plane of Fire to wash the city in fire.

A good Meteor Swarm might do a satisfying amount of damage too.

A Gate can only remain open for one minute, that's not nearly enough time to flood a city the size of Waterdeep with lava.

Quote from 6thLyranGuard >>

A Gate can only remain open for one minute, that's not nearly enough time to flood a city the size of Waterdeep with lava.

 
Given the right angle and pressure it might do more than you think.

I mean technically it depends on how you define destroying a city. If we're talking about getting it empty or unlivable then yes, Gating to the right place of harmful substance can do a lot. A few streams, a small fraction of the amount you're bringing forth,  from a volcano destroys towns in seconds in real life. A minute of a full 20-foot wide hole torrent of the stuff can do a lot - most structures are stone, which lava can melt quickly at the base cause many to collapse, melt and become more molten stone and rock. Even after the Gate itself closes, the rivers of lava and molten rock will still be there, continuing to flow, cause damage and so on. It can actually take MONTHS for lava to full cool - all the while continuing to flow, melt more buildings and render the place uninhabitable long after the gate closes.

As the stuff melts and burns it will also smoke, filling the skies for many, many miles, with toxic fumes and ash - and is actually more lethal than the lava since it spreads further, faster and much more difficult to avoid. Anyone under those clouds for too long (which is still a very short period) will die.

So yeah, 1 minute of a 20-foot diameter column of lava seems more than enough to destroy, or render inhospitable, most or all of a city. Especially if you place it right.

It will cause a lot of destruction, yes.  But you're seriously underestimating how large Waterdeep is is the problem.  Lava flows are not really that fast, relatively speaking, and Waterdeep is not a particularly steep city so it's not to go racing down the streets for long distances.  You don't have a mountain and you don't have an actual volcanic eruption in this scenario, which means that you're not getting the clouds of superheated gas that are racing down the slope at hundreds of miles per hour or lava that's going to be moving particularly energetically, either.  That's what typically causes the real damage in a volcanic eruption.  It's going to be impressive damage in the area of the portal, sure, but it's not going to spread very far.  And yes, it can take months for lava to fully cool, but long before then it will have cooled on its outside edges and stopped spreading damage around.

 You can use Thaumaturgy to make the all the window shutters slam into the walls extremely forcefully, shatter into shards, and ricochet around, killing people.

Quote from Cyb3rM1nd >>

Quote from 6thLyranGuard >>

A Gate can only remain open for one minute, that's not nearly enough time to flood a city the size of Waterdeep with lava.

 
Given the right angle and pressure it might do more than you think.

I mean technically it depends on how you define destroying a city. If we're talking about getting it empty or unlivable then yes, Gating to the right place of harmful substance can do a lot. A few streams, a small fraction of the amount you're bringing forth,  from a volcano destroys towns in seconds in real life. A minute of a full 20-foot wide hole torrent of the stuff can do a lot - most structures are stone, which lava can melt quickly at the base cause many to collapse, melt and become more molten stone and rock. Even after the Gate itself closes, the rivers of lava and molten rock will still be there, continuing to flow, cause damage and so on. It can actually take MONTHS for lava to full cool - all the while continuing to flow, melt more buildings and render the place uninhabitable long after the gate closes.

As the stuff melts and burns it will also smoke, filling the skies for many, many miles, with toxic fumes and ash - and is actually more lethal than the lava since it spreads further, faster and much more difficult to avoid. Anyone under those clouds for too long (which is still a very short period) will die.

So yeah, 1 minute of a 20-foot diameter column of lava seems more than enough to destroy, or render inhospitable, most or all of a city. Especially if you place it right.

Mulmaster has gaping holes to the plane of fire...yet the city stands just 'fine'.  one 20 foot column of lava for one minute just isn't going to do it much at all . yes it takes forever for lava to cool, but cut off the source and its not going to continue to flow when the leading edge cools (which would be pretty fast)...it'll just sit there. even when its flowing it'd be at a snail pace...viscosity is the word i believe.  you know, how people in hawaii were able to step out of the way....from a lava source that pushed out lava for MONTHS...and how the island doesn't actually get erased every few years.

Yeah, lava does not move very fast, if you wanted to gate in deadly liquid, do the river stix, the water immediately kills anyone.

Ah, yes, finally I have the opportunity! I've been preparing for this moment ever since I started DMing!

The first would be to capture the tarrasque with an Imprisonment spell after wearing down its legendary resistances during a fight, and then bringing the gem it's trapped inside into Waterdeep, say a command word to release it, and watch it get destroyed.

The second would take awhile, but to stash Glyph of Wardings with Meteor Swarm stored in them all across the city. You can then trigger them all at once, anywhere in the multiverse, by saying a command word, or performing a specific set of actions. 

The third would be to create a gate spell above Waterdeep to the Elemental Plane of Fire to flood the whole city with lava. This is fairly easy to do, you just need a broom of flying or to be an aarakocra to get above it and cast the spell. Maybe use the Wish spell to try to turn it permanent. 

The fourth would be to be a necromancer, kill a village filled with commoners, and then raise them all as skeletons with multiple castings of Animate Dead, have a simulacrum animate the same amount of zombies, and then find 2 Nightwalkers, use your level 14 ability Command Undead to make them yours and your simulacrum's servants, then go raid Waterdeep. The odds of you winning are fairly high as long as Elminster, Laeral Silverhand, and other such mages are preoccupied. 

The fifth would be to use Wish to teleport all of Undermountain to just 1 mile above Waterdeep, causing the city to crumble into the chasm beneath, and crushing most of the city from the falling dungeon.

The sixth probably won't work, but you could use wish to cast catapult on the city with no weight maximum, causing it to be flung into the air.

The seventh is a bit complicated, and has a high chance of failure and 100% chance of death, but you can use a Wish spell to teleport to level 22 of Undermountain. (You need to bypass Undermountain's anti-teleportation effect, and this is probably the easiest way to do it, unless you can find Maddgoth) On this level there's a tablet that can be used to open a portal to the Far Realm. Attune to this tablet, open a portal to the Far Realm, destroy Waterdeep and probably the world!

I may add more later. 

Edit: After rereading the first few posts and rules, I am now revising to put that the second, fourth, fifth, sixth, and seventh options break these rules. So, the first option is probably the most feasible of these. 

Gather all the most powerful people and use mass suggestion for them to destroy it? 

Yeah, the Gate spell is probably the best way to go. Summon a ton of lava, stygian water, normal water, and a ton of other different combos could work. 

Yeah, this would be about the only way.  They kept the power level of magic a lot lower in this edition.  That way there are no chances of a spell that has been affected by a bunch of metamagic feats causing everyone in the city from taking massive falling damage.  This edition feels a lot less epic, but you do not have to test every source book that comes along for exploits.

Really, the best way to destroy the city with a Gate spell is to open a portal to the Elemental Plane of Earth and bring through as many elementals as possible and have them undermine the city until it falls into the Underdark.

That is by far the best idea.

I could see myself casting earthquake over and over to wreck it. 500 foot fissures would make it pretty easy. 

Quote from JayDan >>

I could see myself casting earthquake over and over to wreck it. 500 foot fissures would make it pretty easy. 

 The original poster clarified that you can only cast the spell once, which is a bummer. 

no no and no again. you release a certain Kenku barbarian into water deep and get the rest of your party (all lvl 20 wizards of course) to cast multiple wall of forces around the city sealing them in. give it an hour then stir thoroughly then leave to cool. you now have a new ruined city for your next campaign

Fill the streets with smokepowder with the help of an Artificer, then cast firebolt on it. 

You've effectively destroyed a city with a cantrip.

How?

Overwhelming the City with a plague. Summon Zuggtmoy or some other entity.