Here are some preferences that you may wish to set initially. See the section Preferences for the complete list of available settings.
Enable Edit ‣ Preferences ‣ Interface ‣ Translation, and choose the Language and what to translate from Interface, Tooltips and New Data.
See Prefs interface translation for details.
If you have a compact keyboard without a separate number pad, enable Preferences ‣ Input ‣ Keyboard ‣ Emulate Numpad. This gives you the 3D view shortcuts regularly used on the number pad.
If you do not have a middle mouse button, you can enable Preferences ‣ Input ‣ Mouse ‣ Emulate 3 Button Mouse. This allows you to hold the Alt or OSKey key while dragging with the mouse, to orbit.
See Input Preferences for details.
File and Paths
At Preferences ‣ File Paths you can set options such as what Image Editor (GIMP, Krita…) and Animation Player to use.
The Temp dir sets where to store files such as temporary renders and auto-saves.
// at the start of each path in Blender means the directory of the currently opened blend-file,
used to reference relative paths.
See File Preferences for details.
Save & Load
If you trust the source of your blend-files, you can enable Auto Run Python Scripts. This option is meant to protect you from malicious Python scripts in blend-files that you got from someone else. Many users turn this option on, as advanced rigs tend to use scripts of some sort.
See Save & Load Prefs auto execution Preference.