"Almost all our desktops, a couple of laptops, cameras and hard drives were stolen," said The Observer editor Richard Kavuma, standing in the ransacked office in Kampala.
"The thieves were probably looking to destroy the evidence (images) that might have incriminated them," he said.
Kavuma, who discovered the break-in early Saturday, said the thieves had also taken the paper's computer server which backed up the office's data files as well as CCTV footage of the premises.
The paper, which is published three times per week, is known for investigative work and has been criticised several times by the Ugandan government.
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"One break-in is bad enough, to have two in six months is particularly hard on us. It's a big blow," James Tumusiime, managing director of Observer Media, said.
Tumusiime described the newspaper, which he co-founded with a collective of journalists, as "a voice of reason" in a "landscape that is politically polarised."
Since elections in February 2016 secured another five-year term for President Yoweri Museveni who has ruled the east African country since 1986, there has been a spate of break-ins targeting activist and civil society organisations.
Kavuma, an award-winning journalist, described the break-in as "an attack on one of the independent voices the country -- it's bad for democracy, it's bad for the media."
Kampala's police today condemned "in the strongest words possible" the break-in at The Observer, and said they would work to apprehend the criminals.
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