Seven cars were involved in the collision near the Leudelange-sud exit towards Esch-sur-Alzette, leaving five people with injuries.
Emergency teams from Esch, Bettembourg, Leudelange, Luxembourg City and Mondercange were dispatched to the scene.
At 3.44pm, the left lane and hard shoulder were closed to traffic as debris was being cleared on the motorway.
The A4 was still closed as of 5.45pm, with tailbacks building up to Croix de Cessange.
Elsewhere, accidents were reported on the A1 towards Trier, between Cents and Kirchberg, as well as on Rue de Feulen in Ettelbruck. Two people were hurt as a result of these incidents.
