The university cited security reasons for sealing off access to the campus in the sixth district of Paris, which was once attended by Macron as well as many other leading figures in France's political elite.
“The main building of Sciences Po Paris is occupied peacefully and on a renewable basis, a decision that was taken during a general meeting of mobilised students,” said a student statement sent to AFP overnight.
Hand-written messages on white banners hanging on the front of the building on Wednesday morning read “Students of Sciences Po against the Macron dictatorship” and “Macron your school is blocked”.
Last week, police were called to the famed Sorbonne university nearby in central Paris to clear out students who were also attempting to occupy the campus, which was the cradle of mass anti-government demonstrations in May 1968.
Students began occupying a handful of universities in March over higher education reforms introduced by Macron that give public universities the power to set admission criteria and rank applicants.
The demonstration at Sciences Po coincides with the fourth round of strikes by railway workers on Wednesday and mass demonstrations and stoppages by public sector workers on Thursday.
The current stand-off between the government and trade union-led opponents is widely seen by political analysts as a critical moment in Macron's 12-month presidency as he seeks to push through wide-ranging reforms to the public sector.
Students and leftist political opponents have criticised Macron's university policy as a violation of the principle of free education for all, but the protests have not yet reached a critical level.
Only four out of 70 universities are completely blocked and nine other university faculties have suffered disruptions, according to government figures on Tuesday.