"From the point of view of some of our traditional partners -- and I am thinking here as well about the transatlantic relations -- there is no eternal guarantee for a close cooperation with us Europeans," Merkel told an audience as she received an honorary university doctorate in Brussels.
Merkel said that "Europe is facing the biggest challenges for decades" with conflicts on its borders like that in Ukraine, but that it would be "naive always to rely on others who would solve the problems in our neigbourhood."
The German leader said Brexit in particular made it important to increase solidarity in the rest of the EU, which has been discussing ways of boosting defence cooperation and other issues in the wake of Britain's shock vote to leave.
"We should see this decision as an incentive to work together (for the goal), to hold Europe together now more than ever, to improve it further and to bring the citizens closer together again," she said.
Around 50 protesters waving placards responded to a call by the Flemish far-right movement Voorpost to protest against Merkel's immigration policies, AFP journalists said.
Police kept them back from the ceremony where she received a joint doctorate from the prestigious Ghent and Louvain universities.
Merkel, who is set to seek re-election later this year, has faced criticism in Europe over her open-door policy for Syrian refugees which critics say encouraged a flood of migrants to Europe.
The migration crisis is one of a series of problems facing the EU, along with the spectre of Brexit, but Merkel said the remaining 27 countries must stand strong.
"We are absolutely in agreement that we cannot let ourselves be divided," Merkel told a news conference after talks with Luxembourg Prime Minister Xavier Bettel before her visit to Belgium.
"The 27 (member states) must act together in the negotiations, but first we await the answer about how Britain wants to design its exit."
Britons voted to leave the EU in a referendum in June last year, but the rest of the bloc has refused to hold any negotiations on their future relationship until Britain formally triggers its departure.
EU nations have warned Britain cannot expect to keep all the benefits of membership of the single market while being able to limit the bloc's signature freedom of movement for people.