Matteo Renzi gambled his political future on the referendum outcome and promised to resign if the reforms were rejected and, in defeat, he is widely expected to fulfill this pledge on Monday.
The "No" vote won 57.1 percent of the vote according to the final count.
"I lost and I say it loud and clear even if I have a lump in my throat because we are not robots," Matteo Renzi, in remarks translated from Italian by CNBC, said on Monday.
"I wasn't able to win, I beg you to believe I did everything I thought was possible at this stage," he added.
Despite an offer to resign, it is possible for Renzi to stay on as prime minister. Sergio Mattarella, Italy's president, could reject his resignation and ask Renzi to reshuffle his cabinet in a bid to form a new government.
The likelihood of this outcome appears very small given Renzi's emotional concession, his previous unwillingness to stay in government in the event of defeat and significant negative sentiment from political opponents as well as members of his own party.