One prominent theme in Simon vs. the Homo Sapiens Agenda is the problem of anonymity in the digital age. The ability to control his identity over email affords Simon some of the benefits of coming out, but prematurely, leaving his real identity to suffer in the closet. Simon learns that anonymity is fragile, but also has the revelation that it is unnecessary and even detrimental to social life.

Another important theme is the scary and unique process of coming out. Simon is initially threatened to be outed, then forced out of the closet by Martin when he publishes a fake coming-out announcement under his name on the school notice board. Though Simon fears abandonment by his peers and family, he finds that their reactions aren't as negative or absolute as he thought. At the end of the novel, he looks forward to a future in which he no longer has to hide, and starts a happy relationship with Bram.

Simon is sixteen years old and coming to terms with his sexuality. He is figuring out who he is and how he wants to live within his local community and his family. While he grows up and changes, his family goes through their own periods of growth and change.

Simon's relationships are tested over the course of the novel. He has to learn where he fits in within his family, how to relate to his friends, and where to find the support he needs for his own struggles. Simon's best friends—Abby, Leah, and Nick—have problems and lives of their own, which Simon realizes he doesn't know much about. He discovers that asking people about their lives is as important as opening up to them about his.

The most prominent example of the use of identity in the novel is Simon coming to terms with his sexuality. Simon realizes that most people assume someone's gender, race, and sexual orientation without any compelling reason to know this for sure. While he tries to deal with his own plans for coming out, Simon sees that all people are faced with a similar struggle. His online friend "Blue" has to reveal to Simon that he is black, while Simon just assumed that he would be white. Simon's default assumption was that Blue would be white and straight, putting Blue in the position of having to "come out" as black.

Agency is a person's ability to act on their own and make their own decisions. In the novel, Simon's sexuality is revealed to Martin, who uses the information as a tool to blackmail Simon. In order to avoid assisting Martin, and to retain the opportunity to come out on his own, Simon is forced to come out much earlier than he wanted to or planned to do.