Sadly, the biggest pre-civil war issue would be slavery. The single item that makes this novel turn up on "banned books" lists all the time is the use of the word "nigger" by Huck and other characters. Mark Twain is trying to show the evils of prejudice, however, and because the setting is pre-Civil War, it is logical that this term would have widespread use. Also, with regard to one of the main characters, the runaway slave Jim, Huck struggles with the fact that although Jim is his friend, he is also a runaway, and technically, Huck should turn him in. Huck wrestles with his conscience over this many times and finally concludes that it would be wrong to turn Jim in, even if it means that Huck will go to hell for harboring a runaway (as he thinks he will, based on his warped religious training).
Huck comes to love and respect Jim as a human being, but he is still prejudiced against black people, a sentiment that was widespread in the southern U.S. where the novel takes place.