Santos said in a statement that Sampaoli, whose contract was due to expire at the end of 2020, tendered his resignation at a meeting on Monday.
The former Argentina and Sevilla boss took charge last December and secured a second-place finish in the 2019 Brasileirao, 16 points behind champions Flamengo.
O Santos FC comunica que, na data de 09/12/2019, em reunião realizada pela manhã no CT Rei Pelé, o treinador Jorge Sampaoli pediu demissão do cargo.— Santos Futebol Clube (@SantosFC) December 11, 2019
Uma vez comunicada a demissão pelo treinador, o caso foi entregue aos departamentos jurídico e de recursos humanos do Clube. pic.twitter.com/PpX0bW0dAI
The 59-year-old has been speculatively linked with the vacant head coach position at Arsenal but reports in Brazil say he has already entered talks with Palmeiras, who finished third in the table.
Racing are also said to be interested in Sampaoli, who won the Copa America with Chile in 2015.