Hamilton topped the opening practice session at the Korea International Circuit in Yeongam, but could only manage the eighth-fastest time in the afternoon running, team-mate Jenson Button was fourth.
Hamilton's best lap was nearly nine-tenths of a second slower than the pacesetting Red Bulls of Sebastian Vettel and Mark Webber.
The Mercedes-bound McLaren driver is 42 points adrift of championship leader Fernando Alonso, and 38 behind second-placed Vettel.
With Red Bull again looking like the car to beat after their domination in Japan, Hamilton is already on the back foot.
And he was pessimistic when asked if he felt he could compete with Vettel and Webber, particularly in qualifying.
"I am not sure, the Red Bulls seem pretty quick, but we will keep pushing," he said.
"Jenson was not that far off the pace today [Friday] and if we get the set-up right and the fuel loads right and everything then maybe we can be competitive.
"I was just struggling a bit with set-up today [Friday]. The first session was fine but for the second one we made some set-up changes and I wasn't able to get a time out of the option tyre, but we will make changes tonight [Friday] and find out (what went wrong).
"In general in the second session the option and the prime tyre were both a disaster for me."
The 27-year-old appeared to be at a loss to explain his lack of pace, as well as his ability in making the super-soft tyres last over a longer run.
"It was such a big difference from the first session to the second session and I only made a small change on the rear ride-height so I don't understand it yet," he said.
"We tried some different things and I was not able to get a good time out of the option or the prime, and on the option I went slower.
"The first session was pretty good and we barely changed anything so I have to figure out what was going on."
Team-mate Button was by far the more content of the McLaren drivers, but is also concerned by the one-lap speed of Red Bull.
He said: "This afternoon on low fuel and high fuel we have made good progress, we are still not quick enough but we are going in the right direction.
"They (Red Bull) have four tenths advantage again in practice and I think they are going to be very difficult to beat in qualifying, they seem to have that strength back.
"Our race pace today seemed to be competitive but over one lap we are still lacking, but I think the adjustments we have made are positive and there is more to come.
"At the moment it does not look like we are as quick as the Red Bulls, but it's only practice. Our race pace feels good and, forgetting about the lap times, our consistency feels good.
"We still have a lot of work to do to fight with the Red Bulls but I think we are going in the right direction."