The protests came as the country marked the 31st anniversary of the People Power movement that deposed dictator Ferdinand Marcos after a 20-year rule. Duterte, a fan of Marcos, made possible the dictator's burial in the Philippines Heroes' Cemetery after he came to power, angering many.
Among the roughly 3,000 protesters was former Philippines President Benigno Aquino, who defended de Lima, his former justice minister, as well as current Philippines Vice President Leni Robredo, also a de Lima supporter, who resigned from Duterte's cabinet after being blocked from meetings when she disagreed with Duterte.
Aquino dismissed claims that members of former administrations were simply trying to destabilize Duterte's regime, a defense often deployed by the current leader.
"How can we be causing destabilization when we are actually offering to help," Aquino said, the South China Morning Post reported.
De Lima says she is innocent of the charges of drug trafficking and operating a prison drug ring while justice secretary and that her arrest is revenge for her decade-long effort to bring Duterte to justice for his alleged connection to the "Davao Death Squad" while mayor of Davao City.
Earlier this week, de Lima called the president a "sociopathic serial killer." In a statement on her arrest, de Lima called his administration "power-hungry, morally bankrupt and abusive," the Manila Times reported.
Duterte has been accusing De Lima of drugs crimes for months, and has conducted a personal campaign against her, making allegations about her sex life as well as the supposed drug ring. Manila Times opinion columnist Marlen Ronquillo called on the government to "show us the money" in a column the day after her arrest.
"Only a money trail will clear all doubts that she really deserved to be called the ‘grandmother of drug lords,'" he wrote.
Father Robert Reyes, who spent the night with de Lima in the Senate before she gave herself up to police, told AFP, "People are afraid. If the government can arrest a powerful person like her, what more the little man? That is the implied message of her arrest."
Several others were arrested along with the senator for alleged involvement in running the prison drug scheme.
Fear did not deter around thousands from protesting her treatment and the war on drugs Duterte launched when he assumed office eight months ago, and which is believed to have killed nearly 8,000 people since then. Fewer than half of those killed were suspected of playing a serious role in the illegal drugs trade. Human Rights Watch has warned repeatedly that the crackdown has emboldened and even sanctioned extra-judicial killings by Philippines police.
"By arresting Senator Leila de Lima on politically motivated drug charges, President Duterte is effectively expanding his 'drug war,'" Human Rights Watch deputy Asia director Phelim Kine said in a statement reported by Channel News Asia.
"Not only Congress, but other pillars of Philippine democracy should be deeply worried," Kine added.
Now, watchers warn of a People Power uprising like the one that toppled Marcos.
"We are taking the matter seriously. We are warning our people about the threat of rising fascism," protest leader Bonifacio Ilagan told AFP. Ilagan, a playwright, was imprisoned and tortured under Marcos' rule in the 1970s.
Left-wing politician Emmi De Jesus said Duterte's opponents would resist "efforts to revert to dictatorship," the BBC reported.
"The pile of bodies in the Duterte government's war on drugs; arrests and killings of political activists; renewed push for death penalty, and militarization of communities affecting women and children is nothing but a U-turn to full-blown fascism," she said.
Duterte won last year's election on a campaign to end drug violence in the country, and pulled no punches regarding his willingness to allow law enforcement bodies to use lethal force while doing so. He has said he could impose martial law to help him eliminate drug rings.