Can D&D 5e Do Non-Fantasy Settings?
Yes, but you will be fighting the system. The further you get from heroic fantasy combat, the more 5e pushes back.
5e can handle sci-fi (Spelljammer, Star Wars 5e conversions), horror (Ravenloft), and modern settings (Dimension 20's Fantasy High). But the system assumes: (1) combat is the primary conflict resolution method, (2) characters grow significantly in power over time, and (3) magic is abundant and reliable. Settings that challenge these assumptions (investigation-focused horror where combat should be avoided, settings where magic is rare and dangerous) will require significant house ruling.
The community's rule of thumb: if your campaign concept involves characters using swords and spells to fight increasingly powerful enemies, 5e will work regardless of whether those enemies are goblins or aliens. If your concept involves characters who should avoid combat, who do not gain significant power over time, or who operate in a world without reliable magic, use a different system. Call of Cthulhu does investigation better. Traveller does sci-fi trade better. Mothership does sci-fi horror better.
Can I Use Adventures From One Edition With Another?
OSR to 5e: easy. 3.5e/PF1e to 5e: moderate. 4e to 5e: hard (completely different monster math).
Converting adventures between editions of D&D is the most common cross-compatibility question. OSR (B/X, AD&D, BECMI) modules convert to 5e trivially: swap the monster stat blocks for 5e equivalents, replace save-or-die effects with appropriate damage, and adjust treasure to 5e economy. The adventure structure, room descriptions, and NPC motivations transfer directly.
3.5e/Pathfinder 1e to 5e conversion is harder because the encounter math is fundamentally different. In 3.5e/PF1e, monsters and PCs scale at roughly the same rate with level (attack bonus, AC, and saves all increase). In 5e, bounded accuracy means low-CR monsters remain threatening longer. A 3.5e adventure designed for four level 8 PCs will likely overwhelm four level 8 5e PCs because the math assumes higher numbers. Start one level higher than the module recommends when converting from 3.5e to 5e.
4e conversions are the hardest because the monster roles (soldier, brute, artillery, controller, lurker, skirmisher) and math operate on a completely different system. 4e monsters have roughly 2-3x the HP of 5e equivalents and abilities designed for tactical grid combat. Do not attempt direct conversion — rebuild the encounters from scratch using 5e monster equivalents.