A member of the Valeria family and related on her father's side to the Julii, Messalina was married at just fourteen to the future emperor Claudius, thirty years her senior. Despite his unpleasant appearance, limp, and tics, Claudius's passion for women was well known, likely an outlet for the numerous frustrations he had endured throughout his life; after all, it would have been impossible to reject the uncle of the then-reigning emperor Caligula as a match. Her union with Claudius produced two children: Claudia Octavia, Nero's future first wife, and Gaius Julius Caesar Octavianus, better known as Nero.

The two assumed the purple in 41 AD, after Caligula's assassination by his Praetorians. Thus, at sixteen, Messalina found herself the emperor's wife and, presumably, exploited her position to build a vast network of clients. Now, a Roman woman who, instead of behaving modestly according to the customs of the mos maiorum, spent her time going behind her husband's back for an unclear purpose was naturally bound to generate a series of defamatory rumours. This practice, already widespread in the Republican era to discredit political opponents, however, when it came to a woman, gave way to a far more unbridled fantasy. Pliny and Juvenal, writing about fifty years later, reported that Messalina, under the nickname Licisca (little dog), prostituted herself at night in brothels, challenging other prostitutes, and that she had committed incest with her brothers.

It could be hypothesised that Messalina's behaviour stemmed from both a lack of affection for her husband and a desire to protect her son, Caesar's heir, against adverse elements within the imperial house, which may have included extramarital alliances or targeted assassinations.

At some point, Claudius must have been informed of his wife's activities by the freedman Narcissus, through the discovery of imperial property in the home of one of her lovers. Claudius himself must have ultimately decreed her death in 48 AD, carried out by a tribune, although Tacitus presents the execution as Narcissus's personal initiative, apparently fearing that the princeps might pardon her. According to Suetonius, Claudius finally declared before the army that he would be killed if he ever decided to remarry: a resolution he did not keep for long, as he married his niece Agrippina, Nero's mother.