I thought the same myself Richard. Very generally we could say that Cairo was a good location for steamboats (it was a boom-town) but a bad one for railroads. There’s a lot of info and discussion at the site at the end of this post.

In a broader sense, Cairo got edged out by the metro areas around it — St. Louis, Louisville, Nashville and Memphis.

I think Cairo had bad geographical site characteristics. From what I can tell by elevation maps of Illinois, there’s no high ground nearby. So it was destroyed by floods several times. Of course low-lying parts of all these rivers cities flood, but in the other cities only the low-lying parts flooded. In Cairo, everything continuously went under.

And sometimes it’s just the luck of the draw. When I was in Ohio I heard a local history lecture about two brothers who argued over building their business in either Portsmouth Ohio or Cincinnati. Both were thriving cities at the time. So one brother went to each town, built a business, bought speculative land, etc. (This is all from memory, so I don’t recall details of dates or what business they were in.) Anyway, you can guess who won out on that deal. Portsmouth is now down to less than half its 1930 population. Was it good judgement on the other brother’s part or just luck?

There are other examples of major rivers meeting where you wonder why there is no big city. At the confluence of the Wabash and the Ohio in southern Indiana — basically nothing. Evansville is 30 miles or so upstream. But you’re still right — there should be a big metropolis there!

https://www.city-data.com/forum/illinois/959318-why-didnt-cairo-illinois-develop-into-7.html