He was born in Piteşti as the son of Mihai Călinescu, a Romanian Army veterinarian, and his wife Ecaterina, née Gherasim. Mihai Călinescu was a landowner and relatively wealthy man. Călinescu attended secondary school and high school in his native city at Ion Brătianu High School then, between 1912 and 1918, studied the Law and Philosophy at University of Bucharest, before taking a Ph.D. in Economics and Political Sciences at the University of Paris, with a thesis on Le change roumain. Sa dépreciation depuis la guerre et son rétablissment ("The Romanian Exchange Rate. Its Depreciation Ever Since the War and Its Recovery").

Initially, Călinescu intended to enter the political scene as a member of the dominant National Liberal Party (PNL), but his views on politics were rejected by its leader Ion I.C. Brătianu. Instead, he joined the Peasants' Party (PŢ), a rising opposition group, falling under the influence of Ion Mihalache. He was first elected to office in 1926, as one of the 38 PŢ deputies in opposition to the second Alexandru Averescu cabinet, and was reelected for consecutive terms until 1937.

After the PŢ merged with the Romanian National Party to create the National Peasants' Party (PNŢ), he stood on the group's left wing, together with Mihai Ralea, Ernest Ene, Mihail Ghelmegeanu, Petre Andrei, and Nicolae L. Lupu. He was the PNŢ local leader for Argeş County, and, when the party came to power with the Iuliu Maniu cabinet in 1928, served as prefect of Argeş before being appointed general secretary to the Ministry of Agriculture by Mihalache (who was titular Minister). In 1930, he was appointed Under Secretary of State in the Alexandru Vaida - Voevod - led Ministry of the Interior.

In the latter capacity, Călinescu oversaw actions against the illegal Communist Party: he ordered the troops to carry out arrests of suspected agitators after the miner strike in Lupeni, and ordered troops to open fire on demonstrators during the Griviţa Strike of 1933.

His equally firm opposition to the fast rise of the fascist Iron Guard (the Legionaries, a group he helped outlaw in January 1931), contributed to the fall of the 1933 Vaida - Voevod government of which Călinescu was a member. The Guard's leader, Corneliu Zelea Codreanu, had by then issued intimidating replies in the far right press.

In opposition to the Gheorghe Tătărescu PNL cabinet, Călinescu warned against the latter's tolerant stance toward the Legionaries, especially after the murder of Ion G. Duca in December 1933 and the desecration of his memorial plate in 1936 ("The Iron Guard is not a movement of the [public] opinion, but rather an association of assassins and foul profaners of tombs").

A staunch ally of France and the United Kingdom and a steadfast adversary of the pro-Nazi Germany movements in Romania, Călinescu also supported King Carol II's move to counter the Guard's success; he first confronted the PNŢ leadership during the elections of 1937, after it signed an electoral agreement with the Guard. Eventually, he defied his party by becoming Minister of the Interior after December of that year, in the short lived Octavian Goga cabinet formed by the National Christians, being immediately expelled from the PNŢ.

He began preparing himself for the confrontation with the Iron Guard. While organizing the early elections of March 1938, he took steps to limit the Guard's propaganda machine, and closed down all press linked to the Guard, causing violent clashes between the movement and representatives of state authorities.

Călinescu remained in office during the authoritarian regime established by King Carol after that date — he was also a founding member of the National Renaissance Front (FRN) created as the sole legal party in December 1938, and was generally seen as very close to Carol. He soon became involved in a virulent dispute with historian Nicolae Iorga, when the latter issued harsh criticism regarding Carol's January 1939 initiative to dress large sections of the society, including Romanian Academy members, in various uniforms (a measure backed by Călinescu); Iorga remarked with irony: "I'm prepared to wear the FRN uniform, but allow me to wear a speared helmet on my head, on which to place [that is, to impale] the Minister of the Interior". Eventually (in May of the same year), Iorga gave in to the demands and became a supporter of the regime.

In May, after witnessing the result of Nazi pressures on Austria (Anschluss), Călinescu decapitated the Guard by ordering arrests of its leaders, beginning with that of Codreanu, as well as many of its members and sympathisers (including Nae Ionescu and Mircea Eliade). Codreanu and other leaders (probably as much as 300 people) were consequently killed in custody; other Legionaries were pressured to sign "declarations of dissociation". Many other Guard leaders, including Horia Sima, fled to various locations in Germany.

On March 7, 1939, after brief stints as Minister of Health and Minister of Education, he replaced the ailing Miron Cristea as Premier, being considered the "man of steel" able to prevent Iron Guard's political violence and to keep Romania out of the pro-German war camp (the nickname "The Man of Steel" probably originated, under the form l'homme d'acier, in essays written by the French journalists Jérôme and Jean Tharaud on Romanian topics). Călinescu was also Minister of the Interior and Minister of Defense. In September of that year, after the invasion of Poland, the pro-Nazi members of Iron Guard alleged that Călinescu and the King Carol planned with the British Intelligence services to blow up the Prahova oil fields, preventing Germany from taking control and using them.

Having been secretly blacklisted at the same time as Nicolae Titulescu, Dinu Brătianu, and General Gavrilă Marinescu, Călinescu was assassinated in Bucharest by Iron Guard members under the direct leadership of Sima (exiled in Steglitz at the time), the last of several attempts (which included an attack on the Romanian Athenaeum and bombing a bridge over the Dâmboviţa River — both of which were uncovered by police).

It seems that the action was carried out with German approval and assistance. On September 1, representatives of Germany, Fascist Italy, and the Iron Guard met in Copenhagen with Mihail R. Sturdza (Romania's ambassador to Denmark and a supporter of Sima), to discuss Călinescu's killing. Some details of the subsequent plan were offered to Romanian authorities by a renegade member of the Iron Guard, Mihai Vârfureanu. A death squad was formed, having as its members the lawyer Dumitru "Miti" Dumitrescu (who had been trained by the Gestapo and returned to Romania through Hungary), the students Cezar Popescu, Traian Popescu, Ion Moldoveanu, Ion R. Ionescu, and the draftsman Ion Vasiliu. Contacting each other in the area around Ploieşti, they initially planned to kill Călinescu, Carol and Marinescu together, and probably aimed to accomplish this in the Prahova Valley.

While passing through the Eroilor area on its return from the Cotroceni Palace, Călinescu's luxury automobile, a Cadillac, was ambushed by that of the assassins, who shot Călinescu, his bodyguard Radu Andone, and his driver (Miti Dumitrescu drove his car into the Premier's, which came to sudden stop as it ran into a cart — Andone was gunned down as he stepped out of the car, and Călinescu as he stood waiting on the back seat; over twenty bullets were recovered from his body). Sima, who is known to have crossed the border illegally in August of that year, was alleged to have disguised himself as a woman in order to witness the actions from nearby; other sources indicate a certain Marin Stănculescu as the covert supervisor. Ironically, Călinescu had never trusted the safety of his Cadillac, and had repeatedly asked Gavrilă Marinescu to allow him use of an armored car.

The group of assassins left the vicinity before the arrival of police forces, and stormed into the Radio Broadcasting Society; holding the employees at gunpoint and cutting short the live airing of a waltz, it announced, through the voice of Traian Popescu, that it had killed the Premier. The message was never broadcast, as, unbeknown to the squad, transmission had already been interrupted by Radio staff.

The vast majority of sources reacting to the events made ample mention of Nazi backing for Călinescu's killers, with the exception of German media (the latter alleged that Polish and British political forces, as a means to pressure Romania into abandoning its neutrality — this version was supported by, among others, Hans Fritzsche).

A harsh repression of the Iron Guard followed under the provisional leadership of Gheorghe Argeşanu — it was inaugurated by the immediate execution of the assassins and the public display of their bodies at the murder site, for days on end. A placard was set up on the spot, reading De acum înainte, aceasta va fi soarta trădătorilor de ţară ("From now on, this shall be the fate of those who betray the country"), and students from several Bucharest high schools were required to visit the site (based on the belief that this was going to dissuade them from affiliating with the Guard). Executions of known Iron Guard activists were ordered in various places in the country (some were hanged on telegraph poles, while a group of was shot in front of Ion G. Duca's statue in Ploieşti); in all, 253 were killed without trial. Călinescu was succeeded by Marinescu as Minister of the Interior and by Ioan Ilcuş as Minister of Defense.

One year later, under the National Legionary State (the Iron Guard's government), Marinescu and Argeşanu, alongside other politicians, were executed in Jilava (September 1940); it was also at that time that the Călinescu family crypt in Curtea de Argeş was dynamited, while a bronze bust of him which awaited unveiling was chained and dragged through the streets of Piteşti. Călinescu's wife Adela was required to hand all of her husband's personal documents, and, in a letter to Conducător Ion Antonescu, claimed to have been repeatedly harassed by agents of Siguranţa Statului.