Santa Fe is the capital of the same-named province and is situated near the confluence of the Rio Santa Fe and Rio Salado rivers, close to the Rio Parana. Santa Fe, one of the oldest cities in Argenina, is opposite the city of Paraná.

Santa Fe's historic quarter around the Plaza 25 de Mayo is home to most of the city's colonial heritage. Here stands the neoclassical Catedral Metropolitana, the colonial-style Iglesia de Nuestra Senora de los Milagros and the Museo Historico Provincial Brigadier General Estanislao Lopez. The museum is named after the great caudillo Estanislao Lopez and houses a collection of paintings, furniture and other artefacts dating back to the 17th century.

Just south of the plaza is the late-17th-century Iglesia y Convento de San Francisco. The church has two-metre-thick adobe walls and a fabulous wooden ceiling constructed without nails as well as a beautiful gold-laminated Baroque pulpit. East of the plaza is the Museo Etnografico y Colonial Juan de Garay which contains many artefacts, particularly ceramics, discovered at Cayasta, where the city was originally founded. It was moved less than a hundred years later due to constant flooding.

What remains of the old city is on show at the Parque Arqueologico Santa Fe La Vieja and the Museo Fundacional Argentina tells the development of the city from pre-Hispanic to the present day.