One of the central themes of American Gods is the difficulty of retaining cultural and spiritual identity in the United States. Over the course of the story, America is repeatedly identified as a land that is "no good for gods." Indeed, we see evidence everywhere that the old gods who have been brought to America are not surviving well. Czernobog and his sisters live in relative squalor, Mr. Jacquel and Mr. Ibis must subsist by running a funeral parlor, and even Easter, who maintains the illusion of flourishing, is fraying at the seams. In the "Coming to America" segments, almost every story presents an instance of hostility to an old culture. America is indeed a melting pot; in the novel, it does not allow old cultures or religions to retain their original splendor when they come from over the sea.

The loss of spiritual identity and potency to technology and and human connectivity is a major concern in Gaiman's novel, embodied by the war between the old gods and the new. It is never specified what exactly the primary antagonist, Mr. World, is the god of, but it is heavily implied that he reigns over globalism, consumerism, and the world market. While he is eventually revealed to really be Loki in disguise, Mr. World has to present a convincing portrayal of (post)modern values to convince true new deities like Technical Boy and Media to take his side against the old gods. Values such as these are hostile to the spiritual values of the old world, and Gaiman shows that Americans today do indeed "worship" technology and media in much the same way that ancient peoples worshiped the gods.

Shadow's story explores the imperfection of romantic love and, ultimately, the acceptance of that imperfection. The contentious nature of Laura's affair is present at every meeting between Shadow and Laura; however, it is clear that Shadow and Laura still love each other and know each other better than anyone. When the narration switches to Laura's perspective, it is obvious that Laura's affair with Audrey's husband was a fleeting impulse, born from the frustration and boredom of life without Shadow. Shadow and Laura's relationship presents the idea that momentary mistakes, even infidelity, cannot necessarily surpass the love between two people—particularly when those two seem perfectly cut out for each other.