Hi, Santa Cruz is arguably the safest neighborhood in Sevilla, day or night. Of course you have to use common sense when walking around in any city at night.
Now, the Macarena on the other hand is not the safest place in the city. Be careful around the Alameda de Hercules at night too.
Take a cab to get back to the Macarena at night. It's not extremely dangerous at night, but I do personally know someone who was mugged at knifepoint in the Macarena at night.
There are plenty of city buses around, but they don't go into the little streets. They stay on the main, wider streets. So, if you want to play it safe, take a cab to get back to your street in the Macarena. Any questions email me espana27@aol.com
Winston