Aniek Nouwen's strike, Fenna Kalma's double and Victoria Pelova's effort ensured victory for the Europeans at Stade de la Rabine in Vannes.
Having lost their tournament opener to France (4-1), the Black Princesses are confirmed out of the tournament ahead of the last group game against New Zealand on Sunday.
The Netherlands, on the other hand, have historically booked a place in the next round as they registered a 2-1 triumph over the islandic country on matchday one.
Ghana coach Yussif Basigi made four changes in Wednesday's starting lineup, with Helena Obeng, Cecilia Hagan, Ruth Anima and Olivia Anokye getting starting berths for the first time.
The new faces, though, could not prevent the Dutch from running riot in their second ever game in the history of the women's U-20 World Cup.
Aniek Nouwen opened the scoring in the 21st minute, before Fenna Kalma registered a four-minute brace before half-time.
Ghana looked better after recess, and after holding their own for 35 minutes, their defence was breached for the last time when Victoria Pelova went through to score her side's fourth goal of the game.
The Netherlands sit top of Group A after France and New Zealand settled for a 0-0 draw in the other group game.
Ghana, on the other hand, occupy the bottom position ahead of their last match against New Zealand on Sunday.