In 1562 Gerolamo Cardano wrote an apology praising Nero in his Encomium Neronis printed Basel. This was likely intended as a mock encomium, inverting the portrayal of Nero and Seneca which appears in Tacitus. In this work Cardano portrayed Seneca as a crook of the worst kind, an empty rhetorician who was only thinking to grab money and power, after having poisoned the mind of the young Emperor. Cardano stated that Seneca well deserved death.

Seneca's plays were widely read in medieval and Renaissance European universities and strongly influenced tragic drama in that time, such as Elizabethan England (William Shakespeare and other playwrights), France (Corneille and Racine), and the Netherlands (Joost van den Vondel). English translations of Seneca's tragedies appeared in print in the mid-16th century, with all ten published collectively in 1581. He is regarded as the source and inspiration for what is known as "Revenge Tragedy," starting with Thomas Kyd's The Spanish Tragedy and continuing well into the Jacobean era. Thyestes is considered to be Seneca's masterpiece, and has been described by scholar Dana Gioia as "one of the most influential plays ever written." Medea is also highly regarded, and was praised along with Phaedra by T. S. Eliot.

Seneca is a character in Monteverdi's 1642 opera L'incoronazione di Poppea (The Coronation of Poppea), which is based on the pseudo-Senecan play, Octavia. In Nathaniel Lee's 1675 play Nero, Emperor of Rome Seneca attempts to dissuade Nero from his egomaniacal plans, but is dragged off to prison, dying off-stage. He appears in Robert Bridges verse drama Nero, the second part of which (published 1894) culminates in Seneca's death. Seneca appears in a fairly minor role in Henryk Sienkiewicz's 1896 novel Quo Vadis and was played by Nicholas Hannen in the 1951 film. In Robert Graves' 1934 book Claudius the God, the sequel novel to I, Claudius, Seneca is portrayed as an unbearable sycophant. He is shown as a flatterer who converts to Stoicism solely to appease Claudius' own ideology. The "Pumpkinification" (Apocolocyntosis) to Graves thus becomes an unbearable work of flattery to the loathsome Nero mocking a man that Seneca groveled to for years.

Seneca remains one of the few popular Roman Philosophers from the period. He appears not only in Dante, but also in Chaucer and to a large degree in Petrarch, who adopted his style in his own essays and who quotes him more than any other authority except Virgil. In the Renaissance, printed editions and translations of his works became Common, including an edition by Erasmus and a commentary by John Calvin. John of Salisbury, Erasmus and others celebrated his works. French Essayist Montaigne, who gave a spirited defense of Seneca and Plutarch in his Essays, was himself considered by Pasquier a "French Seneca." Similarly, Thomas Fuller praised Joseph Hall as "our English Seneca." Many who have considered his ideas not to be particularly original, still argued he was important in making the Greek Philosophers presentable and intelligible. His suicide has also been a popular subject in art, from Jacques-Louis David's 1773 painting The Death of Seneca to the 1951 film Quo Vadis.

Among the historians who have sought to reappraise Seneca is the scholar Anna Lydia Motto who in 1966 argued that the negative image has been based almost entirely on Suillius's account, while many others who might have lauded him have been lost.

Even with the admiration of an earlier group of intellectual stalwarts, Seneca has never been without his detractors. In his own time, he was accused of hypocrisy or, at least, a less than "Stoic" lifestyle. While banished to Corsica, he wrote a plea for restoration rather incompatible with his advocacy of a simple life and the acceptance of fate. In his Apocolocyntosis he ridiculed the behaviors and policies of Claudius, and flattered Nero—such as proclaiming that Nero would live longer and be wiser than the legendary Nestor. The claims of Publius Suillius Rufus that Seneca acquired some "three hundred million sesterces" through Nero's favor, are highly partizan, but they reflect the reality that Seneca was both powerful and wealthy. Robin Campbell, a translator of Seneca's letters, writes that the "stock criticism of Seneca right down the centuries [has been]...the apparent contrast between his philosophical teachings and his practice."

Ten plays are attributed to Seneca, of which most likely eight were written by him. The plays stand in stark contrast to his philosophical works. With their intense emotions, and grim overall tone, the plays seem to represent the antithesis of Seneca's Stoic beliefs. Up to the 16th century it was normal to distinguish between the Seneca the moral Philosopher and Seneca the dramatist as two separate people. Scholars have tried to spot certain Stoic themes: it is the uncontrolled passions which generate madness, ruination and self-destruction. This has a cosmic as well as an ethical aspect, and fate is a powerful albeit rather oppressive force.

Many scholars have thought, following the ideas of the 19th century German scholar Friedrich Leo, that Seneca's tragedies were written for recitation only. Other scholars think that they were written for performance and that it is possible that actual performance had taken place in Seneca's lifetime. Ultimately, this issue cannot be resolved on the basis of our existing knowledge. The tragedies of Seneca have been successfully staged in modern times.