Despair is generally acclaimed as one of Nabokov's better Russian novels, along with Invitation to a Beheading and The Gift (1938), and has a reasonable volume of literary criticism. British author Martin Amis ranked it second on his list of best Nabokov novels, with it trailing only Lolita (1955). However, Nabokov's biographer Brian Boyd seemed to have ambivalent feelings toward Despair, noting that although "Nabokov's sheer intelligence crackles in every line... the book's style... seems sadly lacking in its structure.... It never quite convinces, and page after page that would make one tingle with excitement in another context can here only intermittently overcome one's remoteness from a story whose central premise fails to merit the suspension of disbelief".
Despair is the second Nabokov novel to feature unreliable narration from a first-person point of view, the first being The Eye with the character Smurov. However, The Eye was more of an experiment condensed in a hundred-page novella, whereas Despair takes the unreliable first-person narrator to its fully fledged form, rivaling Humbert Humbert from Lolita, and Hermann is in a sense, Humbert's Russian cousin. Nabokov comments on this in the Foreword to the later edition of Despair, where he remarks that "Hermann and Humbert are alike only in the sense that two dragons painted by the same artist at different periods of his life resemble each other. Both are neurotic scoundrels, yet there is a green lane in Paradise where Humbert is permitted to wander at dusk once a year; but Hell shall never parole Hermann". To put it simply, the reader can never be positive if Hermann is accurately narrating the events because he tends to conflate his own skills and talents while ignoring reality around him.
Additionally, Despair is also a tale of false doubles, one of Nabokov's favorite themes. The very title of the novel announces this theme as French-speaking Nabokov chose a word (despair) which in French means 'some pairs', or simply 'pairs' (des paires). But it also means, so to speak, 'to undo a pair', to 'dis-pair', i.e. the process going on in the novel by which the pair Hermann thought did exist actually revealed itself false. In it, doubling seems to be only an obsession with physical resemblances. Almost all of Nabokov's fictions make ample use of doubling, duplication, and mirroring, such as in Pale Fire and Lolita.
Vladislav Khodasevich had pointed out that Nabokov is obsessed with a single theme: "the nature of the creative process and the solitary, freak-life role into which a man with such imagination is inevitably cast.." Hermann who sees himself as an artist composing the 'perfect murder' fits this description. In a similar fashion, Julian Connolly calls Despair “a cautionary tale of creative solipsism”.