Simon vs. the Homo Sapiens Agenda comes down to several classic tropes and plot elements, framing them in a contemporary plot about the struggles of a young man trying to control his coming out in the digital age. Simon's three friends, Nick, Abby, and Leah, are engaged in a love triangle that becomes more complicated when Martin blackmails Simon into helping him court Abby. Simon juggles the commitments of friendship with the fear of being prematurely outed in a school where gossip travels fast over social media.

At the book's onset, Simon learns that though the internet affords an a degree of anonymity, it is very difficult to preserve. He goes through the usual litany of fears about coming out, including the fear of being rejected by friends and family. In contrast, at the end of the novel, Simon comes to believe that this anonymity is undesirable, learning the importance of living one's true self even if it requires a transformation in one's public identity and social life.