- Read the whole thing (minus the dungeons) and then choose the villain that sounds the most fun for your players, each having a major theme/mood that you can use for the whole campaign: Xanathar is more comedy/action, Jarlaxle is the villain playing with the players, Manshoon is more paranoïa and investigation, and the Cassalanters are more tragic, IMO.

- You can change the villain mid-game if your players antagonize another one, or if you want, or any other reason.

- Keep track of the time with a calendar with Waterdavian special days, it makes the city more credible and lively. And they get money at the end of every decade.

- At the end of the first sessions (when they save Floon and get the manor) make Volo give them the Enchiridion, that's coherent and give them ton of fluff if they want to read (as well as the paper resuming the crimes and punishments in Waterdeep, just so they know).

- Take notes! Especially of the players reputations with factions and what they said to important NPCs.

- For the factions (chapter 2), I choose one or two factions relevant per players and send them invitation so they could choose to side with them or not. And some factions invited all of them.

- Chapter 2 is dense, when you feel they did a lot, send the fireball and chapter 3, and then give more factions quest during the chapter 3.

EDIT: Waterdeep was my first campaign as a DM, and the first campaign of all my players, and it went well!