In the US, my vote would go to Delta at Atlanta. Even before deregulation, DL
used Atlanta as a transit point to move passengers from the origin to final destination. Schedules were coordinated for quick connection times and all of the elements that we now associate with hubs were in place by the mid 1960s. Allegheny (now US) should get an honorable mention, as their operation in Pittsburg and other cities introduced the idea of using regional aircraft to connect passengers from smaller cities to a central point to pick up mainline flights. Allegheny Commuter was one of the first regional airlines as we use that term today.
Once can also not forget KLM, with its huge operation at Amsterdam. KLM was one of the first overseas carriers to very aggresively go after long haul connecting traffic, especially moving passegers from US cities via AMS
to destinations all over Europe and the mid-east. KLM is a large airline from a small country, so this approach was developed out of necessity and AMS
is an ideal location for a european hub - over time, many European and Asian carriers developed hubs based on the KLM model.