Matt Yglesias, thinks the best last line from a novel comes from The Great Gatsby:
So we beat on, boats against the current, borne back ceaselessly into the past.
I agree with him to some extent. But there are some tough choices here. Beckett's brilliant last line in Waiting for Godot has an epigraphic quality that doesn't necessarily mean that it works from a dramatic standpoint; it's more a summation of the play's philosophy than the inevitable emotional beat that concludes its action (or inaction, as the case may be).
As a perpetual Hemingway apologist—put down those lurid biographies and read the damn books, people!—I'm always going to defend the pitch-perfect ending of The Sun Also Rises:
“Yes,” I said. “Isn’t it pretty to think so?”
For what it's worth, I don't think it's fair to include in this list (aren't we discussing novels here?) the best last line of any short story ever written, "The Dead," by James Joyce:
His soul swooned slowly as he heard the snow falling faintly through the universe and faintly falling, like the descent of their last end, upon all the living and the dead.
(A list of the best last lines of short stories is a problem I'd love to grapple with. Off hand, I can think of a bunch to include: "My Mortal Enemy," "The Snows of Kilimanjaro," any number by Denis Johnson and Raymond Carver. What am I missing? I'm not reading a lot of contemporary short stories these days so I freely confess my ignorance.)
In reading the novel list I was taken aback by how many last lines have entered our collective consciousness via Bartlett's quotations (e.g. A Tale of Two Cities, The Adventures of Huckleberry Finn, A Christmas Carol). Stripped of their contexts, these famous quotes become blunted and troublesome. Because of their ubiquity, we can no longer assess them as pure literary constructs; we can't appreciate the functions they were meant to serve within their respective novels.
All in all, though, I'd have to say that skimming these last lines provoked in me a desire to go back and reread books I haven't fingered since college. Absalom, Absalom! here I come.
UPDATE: OK. I'm not going to chicken out here. I have great affection for a lot of these enders as works of genius (1984, As I Lay Dying, Moby Dick, Heart of Darkness), but if forced to pick, my own choice would come down to Gatsby or Ulysses. Frankly, Joyce's polyglot masterwork is not something I find myself reaching for regularly, but the novel ends exactly where it has to end. It utterly fulfills its author's intention. One of the ways you know a book is a masterpiece is when you realize at the conclusion that there was no other possible way this story could have ended. Bloom wins!