The ending of Paradise Lost is one of the most beautiful and depressing scenes in all of English literature. Just think about it: humankind's one chance to have the perfect world (no suffering, no pain, no death, no disease, no angry lions in the forest that might kill you) goes up in smoke! The gates of Paradise are even barred with a "flaming brand," just in case Adam and Eve (the very first human beings ever, according to the Judeo-Christian religious tradition) should get any crazy ideas and try to get back in.
In the last two books of the poem, Adam receives a history lesson from the angel Michael; at the end of the history lesson, Michael leads Adam down from the mountain on which they have been standing. Adam goes and wakes up Eve, and the two of them exit Paradise, holding hands and shedding a few tears. A very big and dangerous world awaits them, but God (in the form of "Providence") will be there to guide them.
First, Adam and Eve's entrance into the world that is "all before them" marks the beginning of human history, from the Christian perspective. It is the beginning of the world of death, sickness, labor, war, etc. that we all know. In a sense, then, the "end" of Paradise is the beginning of human history as we know it now, the time between Eden (the beginning) and the apocalypse (the end of the world).
Second, this departure from Paradise also marks the beginning of the end for older types of literature, such as epic and religious poetry (Paradise Lost is both). Indeed, critics have often noted how English literature underwent many changes in the wake of Paradise Lost; within 40 years satire and comedy were the dominant genres, and within another 50 the novel began its ascendancy. As you can see, none of this happened overnight; it took some time, but eventually writers realized that they either didn't want to be all serious like John Milton, or that everyday life was way more interesting than angels and demons, or that Milton was just better than them and there was no point in trying to outdo him.
Whatever the causes (and there were a ton of them), literature changed a lot after Paradise Lost. It's almost as if Adam and Eve's departure from a supernatural place like the Garden of Eden – remember angels fly down from heaven and hang out here! – corresponds to a decline in literature about religious subjects. Milton didn't "intend" this, but that doesn't mean it's not true.