What's the best neighborhood in Louisville for a first time visitor?

Louisville is a very "easy" city in the sense that if you were to stay at one of the centrally-located downtown hotels you would be able to drive most places within 15 minutes or less! If you are not driving, Uber and Lyft are everywhere.  I wouldn't advise using public transport here. 21C Museum Hotel is exceptional but not cheap, and other options would be the Hyatt Regency Louisville, Hilton Garden Inn Louisville Downtown, or the old-school The Seelbach Hilton Louisville or The Brown Hotel.  Hope that helps! 

The Highlands (Kentucky), without a doubt. There you can find a plethora of independent shops, restaurants, and bars. It is especially nice to walk along Bardstown Rd./Baxter Ave. in sunny weather from May to September. You should also check out the beautiful and historic Cave Hill Cemetery, the final resting place of Muhammad Ali and Colonel Sanders. Other areas to visit are Old Louisville (including the University of Louisville campus) and Crescent Hill. 

Any of the downtown hotels would be good. Fourth Street Live! is eateries and shops specifically if you like to dance and party. Galt House, a riverfront hotel, can sometimes be found on travel sites for a lot less than usual. The Steamboat Belle of Louisville is just a few blocks from here. It is the oldest steamboat still sailing the rivers. There is the Louisville Science Center and other attractions that have artists and shows that are available. The new Yum Center  is there with lots of stuff going on there. Many venues exist to suit any taste. Locals have ethnic neighborhood festivals and it is just a matter of what and when you seek.

Sports, food, history, Speed Museum Garage,  Brown Theatre, and btw, try a hot brown and derby pie while in town. The bat factory is right here  and makes a lot of the bats for the professional players and so are Louisville Bats, the local prepro baseball team. the glass factoryis just around the corner which features a glass blowing shop, art displays, and things glass-based like jewelry. See what's happening at the convention center out be U of L.

The best thing you can do is find out what is going on in town and seek it out. Louisville still has a small town feel and is diverse so that small neighborhood groups do things and the people are southern friendly but you will have to look at ethnic sites that can tell you about local happenings. Depending on when you are here, you can find things going on on the riverfront like the Freedom Festival or things to do with the Derby and its a nice time.

The unfortunate thing is that they are building bridges and roads downtown right now and it is a mess to get around if you don't know what you are doing. Some of the major interstates are closed off and rerouted till further notice. If you fly in, then coming north is the easy route to get downtown. Hope this is some help and best wishes for a great and safe trip. Kathy