The LDU Quito midfielder had been in hospital since the incident on 7 October in the south of Ecuador's capital Quito.
Reports in Ecuador, external said he underwent several operations and spent over a week in intensive care, before passing away on Monday night.
"With profound pain and sadness, we regret to be able to inform you that our dear player Marco Angulo has died," LDU Quito, who play in Ecuador's top flight, said in a statement on Tuesday morning.
"We extend our condolences to his family and to all his loved ones.
"His passing is an irreparable loss that will leave an indelible mark in our hearts."
Angulo, a midfielder for MLS club FC Cincinnati, joined LDU Quito on loan with an option to buy in March.
Angulo made 16 appearances for the club. His last appearance came on 6 October - a day before the car crash.
Angulo made his debut for Ecuador in November 2022, coming on as a substitute in a 0-0 draw against Iraq, and earned three caps for his country.
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"The Ecuadorian Football Association expresses its most profound sorrow for the death of Marco Angulo," a statement from the governing body read.
"Marco was not only an exceptional player but also a very great companion. He leaves in our heart a deep sorrow, especially in those of us who went with him on innumerable trips and to training camps and matches.
"Rest in peace, Angulito."
Also among the dead, according to Ecuadorian reports, was Independiente del Valle footballer Roberto Cabezas, and his friend Victor Carcopa, in the accident.
There were two other passengers in the car at the time. Their condition is not known.
With Angulo's death, three people have now lost their lives as a result of the car crash. The two footballers who had also died were Roberto Cabezas Simisterra and Victor Charcopa Nazareno.
Midfielder Angulo had only his professional debut in 2020 but has already been capped twice by Ecuador. His last appearance had come in a 2-1 win over Australia in March 2023.
A statement praising those who had stood by the young player was issued immediately after last month's car accident.


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