Micro- can give best profits, I played for years that way. But, finally I managed to relax my play a bit more and dabble in automation.
Simplification was how I went about it. For express traffic I look for pairs of cities. These should be of about equal size and as far apart as practically possible, connected by as straight track as practically possible with no grades on the turns. I will go for max carriages, mix of mail and passengers. Wait to fill 4. For 4-house towns it will be wait for 3 out of 5.
For freight, it's better not to mix cargoes. Highest revenue is achieved by dumping a full trainload of one cargo type.
At this moment I would summarize 3 overall strategies for set-and-forget freight.
1. Use it just to provide volume to push city growth. Long distance express revenue is so much higher. Best use in the 19th century. Rising running costs and rot factor make this less practical for a modern game.
2. Industrialize. Buy the factories, and run as short and cheap service, both resource in and finished good out, with the maximum of volume. Focus on the industries. Industrial profits are perhaps a little less, but more stable over an economic cycle.
3. Work the chains as Jeffry suggested. The money maker is hauling finished goods a moderate distance. Manage those end-product demands as first priority. You are in control of supply via how many resources you hook up. Resource hauls should be as short as possible, minimize costs. This is the place to use wait-till-full trains. Then when converted you have a full trainload of say Grain -> Food. Often I will repeat the resource section, but alternate destinations. Food -> City A followed by Food -> City B. This gives time for demand to recover.
The typical map has heaps of resources that are just for eye candy. Automation is accepting this is ok and for #3 to ignore even more of them. I have a plan for distribution ahead of time before connecting a new resource.
A rare few cargoes*, including Food can work as long distance. But said journeys in the 20th century are best if not dead-headed on the way back. That means combining with a different chain. This makes the route more complex, but after a bit of practice it can be setup without headache.
*There is some confusion in the documentation about distance factor. https://forum.dune2k.com/topic/23923-cargo-data-for-v156-ripped-from-exe-file/?do=findComment&comment=395629
At the moment the figures I trust most are in the data included with the download of Jeffry's US History map.
PS. Sorry to say I haven't found time and/or worked out how to do the check I mentioned in the link.