When the First Constitution of Uruguay was signed in 1830, the territory of this department was mostly part of Cerro Largo, one of the nine original departments of the Republic. In 1853 the pueblo (village) of Treinta y Tres was created in its south. It was named after the thirty three honoured patriots who fought for and secured the Independence of the old Provincia Oriental, which became Uruguay. A permanent service of transport by horse-drawn carts between this pueblo and Montevideo was first established in 1866.
On 18 September 1884 and by the Act of Ley No 1.754, the department of Treinta y Tres was created out of parts of the departments of Cerro Largo and Minas (the actual Lavalleja Department).