Can you get all the endings in one playthrough of Silksong?
Not in a single, uninterrupted run — Silksong has five endings, most of them mutually exclusive, and one specific choice locks you into the game's final act, closing off the earlier endings on that save for good.
One choice locks out three other endings for good — reload before it and you can still see most of them.
Spoiler warning: this answer only covers the structure of Silksong's endings — how many there are and how they lock each other out — not what actually happens in any of them.
No, not on one uninterrupted trip through the credits. Silksong has five endings in total, and sources agree the earlier ones are mutually exclusive on a single save: picking one of the early routes through Act 2 closes the door on the others, because the game commits your save the moment you clear the boss tied to that ending.
The real point of no return is the choice that pushes the story into the game's final act. Once you clear that fight, your save advances permanently — you can't go back and pick up one of the endings that were only available earlier in Act 2, even by killing yourself or reloading. Everything before that fight is more forgiving: multiple guides note that if you reload your save before beating the boss that locks in an ending, you can walk back up to that same fight and choose a different path instead, seeing several of the early endings on the same save without starting over. Our boss order guide has the fights that gate each route.
What still needs a second playthrough
The two endings tied to Act 3 — the game's true ending and its secret epilogue — sit past that point of no return, so if you've already committed to one of the earlier Act 2 endings, reaching them means starting a fresh save (or a New Game Plus-style run) rather than reloading an old file. Guides don't fully agree on whether every one of the five endings can be seen through reloads alone or whether full completion realistically needs more than one save; if you're chasing all five for completion purposes, the safer plan is to keep an early backup save before the first ending-locking fight and treat one full playthrough as covering Act 3 alone.