"Thanatopsis" is a meditation both on nature, and on the nature of death. The speaker first counsels the reader to be aware of the healing effect that contemplating the beauty of the outside world imparts to us. This theme, however, is a mere prelude to the more significant point regarding death, elaborated throughout the poem.

In death, the speaker indicates, we are merged with both nature, and with all the people in the history of the world who are already dead. The enormity of this fact is, perhaps surprisingly, one seldom mentioned by poets, and an idea most of us never objectively contemplate at any time in our lives. Ultimately, however, Bryant's theme is a simple one that has been expressed countless times in religion, philosophy, and literature: that death is inevitable and need not be regretted or feared. The theme, ironically, contains within itself the paradox of human thought in which the central fact of existence—that we are all on the road to death—is somehow shunted aside and treated as if it were an anomaly, though it's going to happen to all of us and therefore must be accepted.

Bryant's theme is one that glorifies death, because in death we become one with both nature and the past dead, including mankind's greatest representatives. His thought has much in common with that of Keats's "Ode to a Nightingale," in which the speaker extols the world of death symbolized by the bird, rhapsodizing "Tender is the night!" though the conclusion of Keats's Ode is ambiguous, for the nightingale is said to be immortal, not "born for death." "Thanatopsis," however, is a plainer, more straightforward view of the end that all of us face.

Its theme is one of ambivalence, nevertheless, because the cold grave is first described as the "narrow house" that "makes thee to shudder." It's reminiscent of lines from Shakespeare's Measure for Measure in which Claudio speaks of the grave as the place we go "to lie in cold obstruction and to rot." But Bryant transforms this sense of doom and physical terror into one of a kind of resigned happiness. Even if there is oblivion in death, it is one in which we are reunited with all of humanity and the entire cosmos, so we should look forward to it just as a sleep in which we are to "lie down to pleasant dreams."