What's the best (non-Star Wars) sci-fi system/setting for fans of D&D 5e?

[ProphetSword]

D6 Space is free. All the fun of the Star Wars D6 mechanics without Star Wars being attached to it.

 

[Tony Vargas]

What's the best (non-Star Wars) sci-fi system/setting for fans of D&D 5e?

The most D&D-like sci-fi games were Metamorphosis Alpha and Gamma World, both contemporary TSR offerings with multiple editions since. They can tend to be a little gonzo or sci-fantasy. The 2nd or 4th editions of Gamma World might be the best for you. The 1st was very rough and chart-based. The 3rd & 5th weren't D&D-like at all. The 6th (if there could be said to be one, was either a d20 Modern licensed travesty by S&SS, or the 3e-like Omega World mini-game from the pages of Dragon/Dungeon - when they were combined). The 7th is more 4e-like, and very heavily encounter-based with mostly-random character generation.

The 4th edition of Gamma World was cleaned up substantially from the 1st & 2nd, and presaged some 3e/5e-style rules. It would probably convert to 3.x/d20/5e fairly easily.

It's a Friday night group with a mix of casual players and tabletop RPG lifers.

Gamma World lends itself to casual 'beer & pretzels' play, and could be a nostalgia kick for some of your lifers.

I'm looking for something set IN SPACE! Umbran used the term "space opera" which I haven't heard used in a while.

The was an old RPG called Space Opera, it was pretty terrible. ;( Metamorphosis Alpha is technically in space (it's a riff off Aldiss's 'Starship,' really). Star Frontiers might do it for you.

 

[LordEntrails]

I'd recommend you take a look at Star Frontiers. I loved it when it came out. It even has rules for ship to ship combat and a board game (Knight Hawks). Though the rules for ship combat defies the laws of physics, I know a couple decades ago their was a fan based (?) revision of the rules to generally obey the laws of physics.

 

[Herobizkit]

No fans of d20 Modern? That plus the Future rulebook would do wonders as the mechanics are kind of the same. There'd need to be some jury-rigging, but not by a far stretch.

We even have d20 Modern to thank for Backgrounds - they were listed as Occupations back then.

Or, be even more creative - just use the classes as-is and slide in some sci-fi fluff.