We have ourselves two titles to sort through with this book since The Knife of Never Letting Go is the first book in a series called Chaos Walking. But let's take it piece by piece.
As far as Chaos Walking goes, this is referenced in Chapter 2 when Todd says that "the Noise is a man unfiltered, and without a filter, a man is just chaos walking" (4.34). The series title, then, is a reference to that chaos inside our heads and what happens when it is broadcast to the entire world.
Now for the title of this specific installment in the series. The Knife of Never Letting Go is a shout-out to the infamous knife Todd carries with him. In Chapter 6, Todd says: "I never let go of the knife" (6.58), and this is pretty much true until it disappears into Aaron's cold, dead body. The knife is pretty epic when it comes to symbolic punch, so be sure to read up on it over in the "Symbols" section. For now, though, we'll just note that the knife is all about Todd's coming of age process, and the title clues us into just how important this blade is.