Kim Seung-won's exit follows the withdrawal of Yong Hye-in as nominee for gender-equality minister on Sunday, in the latest fallout from Lee's cabinet reshuffle in late August.
Kim, who said he did not want to add any burden to Lee's administration, criticised a conservative lawmaker who had accused him of lobbying regulators over a drug trial and of financial irregularities. Kim has denied the allegations.
"I gravely accept that I did not meet the public's expectations, and I will deeply reflect on my shortcomings," Kim told a press conference, Reuters reported.
A Gallup Korea poll released on Friday put Lee's public approval at 37%, the lowest since he took office in June 2025, a decline pollsters have partly linked to criticism over his personnel appointments.
At a press conference on Friday, Lee acknowledged shortcomings in his administration's screening of nominees. "We are currently working to reexamine our personnel system," the president said.