Portugal – the European champions – were upstaged by Netherlands, who delivered Ronald Koeman's first win since becoming Oranje's coach in February.
Netherlands failed to qualify for the World Cup in Russia but they were too good for Portugal, who had Joao Cancelo sent off in the second half, thanks to goals from Memphis Depay, Ryan Babel and Virgil van Dijk.
Reflecting on the friendly defeat, Santos told reporters: "I could have done better, but the responsibility for defeat is mine.
"It was I who chose the players, had observed the opponent, set up the strategy so that we had possession of the ball and I think in the initial 10 minutes we had the ball and circulated well.
"We conceded a goal and from there things got more complicated. They explored the side aisles well and had many difficulties in the first half.
"The overall behaviour was not adequate and we could not go on a counter-attack. We talked to the players at half-time and in the second half we were a different team in every respect.
"We did not allow spaces to the opponent, except near the end. With 10 players on the pitch we had a bit more difficulties, but we kept trying to reach the goal and we had three or four chances. We deserved a goal or two."
Meanwhile, Netherlands boss Koeman added: "We started our project last week. We decided to play with a system totally different from the one we used in the selection for many years. We presented a midfield with three players.
"The team made an excellent game and left few spaces between the lines. Portugal had many problems finding spaces. The difference between tonight's game and last Friday's [a 1-0 loss to England] was that we were more comfortable and scored quickly.
"The team was more confident and more adapted to the new system. The result of tonight's game makes things easier."