As @stewl said: where you set the origin in Fusion and where you set the work origin on the cnc must be exactly the same.
If you’re milling away excess from the top anyway, or your top is flat, then the top is easiest. If you’re top side isn’t completely flat, it sometimes can be more convenient to set it at the level of the bottom plate. But I almost never do it that way.
You preferably set the origin on a spot where you don’t mill away anything. For example if you mill something away and then you need to change bits (because you do multiple passes with multiple bits or you break one) you will have a very hard time setting the work-origin (z-height) again. as the length of the different bits will be different.
For the multiple passes. It depends on the type of milling operation you’ve chosen, but in the config of the toolpath you usually have a tab called “passes” or “cycles” (see screenshot)
Look for something indicating the maximum step-down. For almost every parameter in Fusion, if you hover over it, you’ll get an explanation of what it means.
Don’t go too wild with the stepdown. Depending on the material hardness, the sharpness of your bit and work speed I rarely go deeper than 1mm per operation. Occasionally 2mm, but that’s on softer materials. Personally I prefer to increase the speed over the depth of cut. But again, depends on the materials you’re working with.
I don’t know how thick your material is and how deep those cuts are in the picture, but it looks like you will be cutting too aggressively.
I would suggest your read this topic started by @sdj544 first: Some info on cnc tool changes and combo cnc/laser projects it contains a lot of very useful tips on cnc & laser jobs.