If I were to install and run Debian Linux from an SD card or microSD card, would this be less reliable than running from a regular HDD (e.g. a 2.5" Western Digital Blue)? The system and home folders would all be placed on the SD card.

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    Raspberry Pis run off SD cards and they're fine – Dmitry Kudriavtsev Jan 28 '17 at 23:17

It will only be limited by the quality of the SD card and slot. The SD card should at least have a much lower latency than your rotating hard drive.

This is an approved Debian installation method, as shown here:

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