Prieto was opposed to Francisco Largo Caballero's line of partial collaboration with the dictatorship of Miguel Primo de Rivera.

[5][6] In that matter, Prieto was supported by Largo Caballero's wing of the party, as the latter believed that the fall of the monarchy was necessary so that socialism could rise to power.

[9] Unlike Largo Caballero, he opposed the general strike and the failed armed rising in October 1934,[dubious – discuss] but he again fled to France to escape possible prosecution.

Prieto gave a thrilling campaign speech in Cuenca on 1 May 1936, prior to the 3 May repetition of the February 1936 election in the district in which the Popular Front would face among the right-wing rival José Antonio Primo de Rivera and, after the resignation of General Francisco Franco as candidate, Manuel Casanova.

[12] In words directed towards the firebrand faction of Largo Cabrello, Prieto asked for moderation, discipline and the disregarding of revolutionary excesses that would put the democratic government in peril.

[12] The speech in which Prieto also displayed a deep sense of patriotism (he claimed to "carry Spain within his heart" and "in the marrow of his bones"[13]) was celebrated by the republican press, and it was received well even by José Antonio, then in prison.

[14] After the beginning of the Civil War, when news of the ruthless and systematic executions of Loyalists by the Nationalists, as part of General Mola's policy of instilling terror in their ranks, began to filter to the areas held by the government, Prieto made a fervent plea to Spanish republicans on 8 August in a radiocast: Don't imitate them!

[17] However, historian Julius Ruiz argues that Prieto was not necessarily a steadfast moderate, as he held that Republican victory would require stripping the Church, capitalists and army of their power as they were deemed collectively responsible for the rebellion.

[18] In September 1936, after the fall of Talavera de la Reina, in Toledo Province, to the rebels, Largo Caballero became the head of the government, and Prieto became Minister of Marine and Air.

Maritime access for Soviet material aid was effectively cut off by the attacks of Italian submarines,[21] and the French border remained closed.

In Mexico, he wrote several books, such as Palabras al viento (Words in the Wind, 1942), Discursos en América (Discourses in America, 1944) and at the end of his life, Cartas a un escultor: pequeños detalles de grandes sucesos (Letters to a Sculptor: Small Details of Great events, 1962).