One of the major themes in "The Prologue" is writing and the drive to write. Dudley (or Bradstreet, as she is more usually known) refers throughout the poem to her own muse and to "the Greeks," referencing Calliope, one of the nine Muses in Greek tradition. In Bradstreet's mind, the urge to write and create is almost a living thing, characterized as a muse who, in Bradstreet's case, may be rather lacking but still has a deep desire to sing and "shine." Bradstreet is eager not to offend the people she is addressing in this poem—men, the usual wielders of "pens," as women were more likely to be wielding "needles"—and she states that her own talent is much less than that of men. However, Bradstreet is very clear that if she is allowed to improve and practice, she may be able to offer something, in the same way that the "sweet-tongued" Demosthenes (a famed Greek orator) was once lisping but grew to excel at what he did.

Another major theme, as hinted at above, is sexism. Bradstreet's goal in writing is to express her frustrations at the role into which society has placed her. She knows that men see it as a threat to them if they allow women to be good at something which is understood to be a male pursuit. For this reason, Bradstreet is very careful in her choice of expression. She states that she herself is far from "perfect," her muse "broken," and that men "have precedency and still excel." She seeks to assure the male imagined reader that, if women are allowed to "be what they are," this would not diminish men and their abilities in any way. Rather, in Bradstreet's view, it is unfair of men to keep women from expressing themselves purely because those women are not "perfect" and may produce inferior works to those written by men. Her final note states that, by contrast, if men allow her to produce her "ore," her raw material, it will actually make their "gold" shine all the brighter.

To the modern reader, there is considerable pathos in Bradstreet's words and the attitude she is forced to take in order to be allowed to express herself. The only way she feels able to beg for a chance to write is by thoroughly acknowledging the inferiority of her talent to that of all men.