What is the significance of the title Wise Blood?

Quick answer:

The title of this novel can be interpreted in a number of ways, but ultimately O'Connor seems to be making the point that there is a divine force that we cannot avoid and that even the most rebellious free spirit will eventually have to submit.

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This is a very complex novel, and we can see the title working on a number of different levels of meaning. Hazel Motes claims he has "wise blood," and this is what makes him so different from others and he determines to try and live his life the way that he wants to, with perfect control rather than believing that he has a destiny and that his free will is limited. Note what Hazel says to another character and how this reveals his views on free will:

“You might as well go one place as another," he said. "That's all I know.”

Ironically, however, it becomes clear that his attempts to try and do this actually reinforce the way in which free will is profoundly curtailed and, as Hazel tries to live his life by avoiding Jesus and trying to persuade others that he does not exist and that he does not have any claim on our lives, his presence in their lives actually makes them question their own beliefs more and often they concede that they have met Jesus through meeting Hazel. There is an ironic twist then in Hazel: he does have "wise blood" that makes his character something that brings others closer to the divine, even though he interprets his wise blood in a very different way. O'Connor seems to present God as an unshakeable reality in this story, as befits her strong religious beliefs, and that even if we set ourselves to run away from him, God will only take that and use it to glorify his name yet further.

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