Honestly, the way I see it, it might be good to play something you are interested in keeping playing. It may be just my experience, but I see a lot of system and genre inertia, where the players aren’t willing to switch systems that easily.

Familiarity with the world lore will be more important in the long run. In the short term, remember that players want to play, they want to buy into the world, or, as Matt Colville put it, they have “willing suspension of disbelief”.

As a sidenote, if you want to play D&D 5e or similar tactical medieval fantasy games, i strongly suggest watching the Running the Game videos in Matt’ YouTube channel (found here). Start from the beginning, he takes you step by step in designing a first dungeon to dip your toes in the DMing water.

Welcome to the hobby!

Rather than a specific system or style, I think the important thing is what gets you and your players excited. Pick a genre or theme that you are your players are into, then find a system that matches that. Once you get into it a bit more you can start digging into different styles of RPGs because you’ll have more context for what it all means and some idea of what you all like.

I like rules light systems because they’ve got a shorter “time to table”, but if everyone is very excited to play DnD, then DnD works because it’ll keep everyone motivated and engaged.

Some ideas:

Sci fi horror game along the lines of Alien: Mothership

Hardscrabble, fools forced to delve into dangerous dungeons and weird woods to make a living: Cairn

Grannies solving murder mysteries a la Miss Marple: Brindlewood Bay

A gang of thieves in a Dishonored-esque whale oil powered city: Blades in the Dark.

A gang of thieves flying a space ship in a star wars or firefly styled galaxy: Scum and Villainy

A doomed world undergoing heavy metal apocalypses: MÖRK BORG, or CY_BORG for the cyberpunk version of that.

Buffy and friends taking down vampire threats, or Mulder trying to find the truth that’s out there: Monster of the Week

Personally I’ve had really good luck introducing new players with Mausritter. The physical version is gives people a tactile card based inventory, the digital version is totally free. It’s super easy for people to get into the head space of tiny mice! There are also tons of fantastic modules to run which makes your job as a DM a lot easier.

This comment got a bit away from me, but I’ve run and played a ton of different systems, so if you have some idea of what you think you and your players will be into I can maybe point you in a more specific direction.

I would opt for a homebrew setting on an earth-like world. The reason is that, having the world be earth-like means there won’t be any misunderstandings about the basic rules of the physical world. Using your own setting means that you won’t have to fight up hill against any assumptions people might have with regards to cultures in that world.

I would go for a good old Call of Cthulhu style investigation. It’s more interesting than fighting monsters, and % system is fairly easy to understand.

System: Fiasco is an amazing system for new players. It’s a GM-less system to get roleplaying with the training wheels on. Once people are comfortable RPing, then move on to any system you know the rules for. It can be played in basically any setting.

Setting: Whatever your players are into and you want to run. Whether it’s sci-fi, fantasy, alternate history or anything else, ask and get a feel for the genres your players like. Stuff like favourite TV shows & movies is great to get an idea.