The accident happened at 5:05 a.m. in the eastbound lanes of the expressway at the Shelter Rock Road overpass in North Hills.
A delivery truck crashed head-on into a bridge abutment and rolled onto its side.
Video from NewsCopter 7 showed extensive damage to the truck.
The driver and sole passenger of the box truck, both men, were pronounced deceased at the scene.
All eastbound lanes were closed at New Hyde Park Road as police investigated and crews worked to remove the wrecked truck.
The roadway reopened just after 1 p.m., but drivers were warned of heavy residual delays.
The Nassau County Police Homicide squad is investigating the incident, and detectives are asking anyone that witnessed the crash to contact Nassau County Crime Stoppers at 1-800-244-TIPS or call the Homicide Squad at 516-573-7788.
All callers will remain anonymous.
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