exactly the same as yours:

#!/usr/bin/env -S nix shell nixpkgs#hello nixpkgs#cowsay -c bash
hello | cowsay

the same as your example above:

#!/usr/bin/env -S nix shell nixpkgs#hello nixpkgs#cowsay -c bash
hello | cowsay

huh, maybe some quirk of macos Lix then? the nix-on-droid example worked with Lix 2.93.3 for me but my Mac with Lix 2.93.3 is also giving me a similar error

§ /tmp/test.sh
path '/tmp/test.sh' does not contain a 'flake.nix', searching up
error: could not find a flake.nix file 

also reading the manpage it seems like -S shouldn't even be needed on Darwin but is probably more portable with it. but with or without, seems to want a flake.nix file which afaik shouldn't be necessary with a fully qualified flake ref like github:nixos/nixpkgs that I was trying

Aha! I've figured something out, this is not a Lix issue but indeed a cursed macOS shebang quirk. You can see it more obviously with one like this:

#!/usr/bin/env -S echo nixpkgs#foo nixpkgs#bar

The man pages for env claim (seemingly incorrectly) that # characters only matter at the beginning of a split argument, and can be escaped with \#: https://ss64.com/mac/env.html

This StackExchange question has some more details about a similar, related issue: https://unix.stackexchange.com/a/774145
and it seems macOS simply copied man pages from BSD even though the behavior is different :( so the best bet might be something like the "polyglot" script they suggest for JS there, if you can figure out how to adapt it for your use case.