Pătrășcanu was born in Bacău to a leading political family, as the son of Poporanist figure Dimitrie D. Pătrășcanu (Lucrețiu's mother was a scion of the Stoika family of Transylvanian petty nobility). He became a Poporanist and later a socialist in his youth, joining the Socialist Party of Romania in 1919, and working as editor of its newspaper, Socialismul (1921). Professionally, he was educated at the University of Bucharest's Faculty of Law (graduated 1922) and at the University of Leipzig (earning his Ph.D. in 1925).
Increasingly radical after the success of the October Revolution, he was one of the original members of the PCR (known as PCdR at the time) in 1921, Pătrășcanu and Elek Köblös were the only two representatives of the group to the 4th Comintern Congress in Moscow (November–December 1922) who had been members of the Socialist Party. Alongside the former socialists and the wing of members in exile were Ana and Marcel Pauker, both of whom opposed the former socialist group; Ana Pauker was to lead the so-called Muscovite wing of the party after she decided to remain inside the Soviet Union. Back in Romania, Pătrășcanu was arrested and imprisoned at Jilava in 1924 (the year when the party was outlawed); he went on hunger strike until being relocated to a prison hospital.
At the Kharkiv Congress of 1928, where he was present under the name Mironov, Pătrășcanu clashed with the Comintern overseer Bohumír Šmeral, as well as with many of his fellow party members, over the issue of Bessarabia and Moldovenism, which was to be passed into a resolution stating that Greater Romania was an imperialist entity. Pătrășcanu argued:
Moldovans are not a nation apart and—from a historical and geographical point of view—Moldovans are the same Romanians as the Romanians in Moldavia . Thus, I believe that the introduction of such a false point renders the resolution itself false.
With Imre Aladar, Eugen Rozvan and two others, Pătrășcanu was elected to the Chamber of Deputies in May 1931 as a candidate for the Workers and Peasants' Bloc, an umbrella group masking the outlawed party. Later in the same year, the 5th Party Congress (held in Soviet exile, at Gorikovo), chose him among the new Central Committee members while Alexander Stefanski rose to the position of general secretary.
In 1932, he was involved in polemics at the Criterion group, where he and his collaborator Belu Zilber defended a Stalinist view of Vladimir Lenin in front of criticism from the right-wing Mircea Vulcănescu and Mihail Polihroniade, as well as from the Austromarxist perspective of Henri H. Stahl.
Pătrășcanu again served as the PCdR's representative to the Comintern in 1933, and 1934 (remaining in Moscow until 1935), during which time he is thought to have developed doubts about Stalinism itself. He put these questions aside in order to prioritize opposition to fascism, and remained active in the PCR. In 1936, he was heading the defense team of PCR members who were facing the much-publicized Craiova Trial, but was himself denounced as a communist and consequently handed the position to Ion Gheorghe Maurer.