They say both men were in an orange Mini Cooper convertible that collided with six other vehicles, all parked and unattended, as it travelled south towards Little Horsted roundabout on the A22.
One man, aged 26, was from Maresfield, and the other, 27, from Crowborough. Both were taken by ambulance to the Royal Sussex County Hospital, Brighton, where they are being treated for serious injuries.
Lewes Road was blocked close to Ridgewood post office and road closures were put in place either side of the scene. These were eventually lifted at 2.18am.
Officers now want to talk to anyone who witnessed the crash or who may have seen the orange Mini or its occupants prior to the incident.
It is believed they may have visited a pub in Uckfield earlier in the evening.
Anyone with information, or who may have relevant closed circuit television (CCTV) or dash-cam footage, is asked to contact police online or by phoning 101, quoting Operation Seasalter.