The overwhelming majority of guilty sentences with repentance seem to have consisted of penances like wearing a cross sewn on one's clothes or going on pilgrimage. When a suspect was convicted of major, wilful, unrepentant heresy, canon law required the inquisitorial tribunal to hand the person over to secular authorities for final sentencing. A secular magistrate, the "secular arm", would then determine the penalty based on local law. Those local laws included proscriptions against certain religious crimes, and the punishments included death by burning in regions where the secular law equated persistent heresy with sedition, although the penalty was more usually banishment or imprisonment for life, which was generally commuted after a few years. Thus the inquisitors generally knew the expected fate of anyone so remanded. The "secular arm" didn't have access to the trial record of the defendants, only declared and executed the sentences and was obliged to do so on pain of heresy and excommunication.

While the notational purpose of the trial itself was for the salvation of the individual soul, allegedly by persuasion, according to the 1578 edition of the Directorium Inquisitorum (a standard manual for inquisitions) the penalties themselves were preventative not retributive, thought to spread an example by terror: " ... quoniam punitio non refertur primo & per se in correctionem & bonum eius qui punitur, sed in bonum publicum ut alij terreantur, & a malis committendis avocentur (translation: "... for punishment does not take place primarily and per se for the correction and good of the person punished, but for the public good in order that others may become terrified and weaned away from the evils they would commit").
Beginning in the 19th century, historians have gradually compiled statistics drawn from the surviving court records, from which estimates have been calculated by adjusting the recorded number of convictions by the average rate of document loss for each time period. Gustav Henningsen and Jaime Contreras studied the records of the Spanish Inquisition, which list 44,674 cases of which 826 resulted in executions in person and 778 in effigy (i.e. a straw dummy was burned in place of the person). William Monter estimated there were 1000 executions in Spain between 1530–1630 and 250 between 1630 and 1730. Jean-Pierre Dedieu studied the records of Toledo's tribunal, which put 12,000 people on trial. For the period prior to 1530, Henry Kamen estimated there were about 2,000 executions in all of Spain's tribunals.

Italian Renaissance history professor and Inquisition expert Carlo Ginzburg had his doubts about using statistics to reach a judgment about the period. "In many cases, we don't have the evidence, the evidence has been lost," said Ginzburg.

Before the 12th century, the Catholic Church suppressed what they believed to be heresy, usually through a system of ecclesiastical proscription or imprisonment, but without using torture, and seldom resorting to executions. Such punishments were opposed by a number of clergymen and theologians, although some countries punished heresy with the death penalty. Pope Siricius, Ambrose of Milan, and Martin of Tours protested against the execution of Priscillian, largely as an undue interference in ecclesiastical discipline by a civil tribunal. Though widely viewed as a heretic, Priscillian was executed as a sorcerer. Ambrose refused to give any recognition to Ithacius of Ossonuba, "not wishing to have anything to do with bishops who had sent heretics to their death".

In the 12th century, to counter the spread of Catharism, and other heresies, prosecution of heretics became more frequent. The Church charged councils composed of bishops and archbishops with establishing inquisitions (the Episcopal Inquisition). Pope Lucius III issued the bull Ad Abolendam (1184), which condemned heresy as contumacy toward ecclesiastical authority. The bull Vergentis in Senium in 1199 stipulated that heresy would be considered, in terms of punishment, equal to treason (Lèse-majesté), and the punishment would be imposed also on the descendants of the condemned.

The first Inquisition was temporarily established in Languedoc (south of France) in 1184. The murder of Pope Innocent III's papal legate Pierre de Castelnau by Cathars in 1208 sparked the Albigensian Crusade (1209–1229). The Inquisition was permanently established in 1229 (Council of Toulouse), run largely by the Dominicans in Rome and later at Carcassonne in Languedoc.

In 1252, the Papal Bull Ad extirpanda, following another assassination by Cathars, charged the head of state with funding and selecting inquisitors from monastic orders; this caused friction by establishing a competitive court to the Bishop's courts.

Historians use the term "Medieval Inquisition" to describe the various inquisitions that started around 1184, including the Episcopal Inquisitions (1184–1230s) and later the Papal Inquisitions (1230s). These inquisitions responded to large popular movements throughout Europe considered apostate or heretical to Christianity, in particular the Cathars in southern France and the Waldensians in both southern France and northern Italy. Other inquisitions followed after these first inquisition movements. The legal basis for some inquisitorial activity came from Pope Innocent IV's papal bull Ad extirpanda of 1252, which authorized the use of tortures in certain circumstances by inquisitors for eliciting confessions and denunciations from heretics. By 1256 Alexander IV's Ut negotium allowed the inquisitors to absolve each other if they used instruments of torture.

In the 13th century, Pope Gregory IX (reigned 1227–1241) assigned the duty of carrying out inquisitions to the Dominican Order and Franciscan Order. By the end of the Middle Ages, England and Castile were the only large western nations without a papal inquisition. Most inquisitors were friars who taught theology and/or law in the universities. They used inquisitorial procedures, a common legal practice adapted from the earlier Ancient Roman court procedures. They judged heresy along with bishops and groups of "assessors" (clergy serving in a role that was roughly analogous to a jury or legal advisers), using the local authorities to establish a tribunal and to prosecute heretics. After 1200, a Grand Inquisitor headed but did not control each regional Inquisition. Grand Inquisitions persisted until the mid 19th century.
Only fragmentary data is available for the period before the Roman Inquisition of 1542. In 1276, some 170 Cathars were captured in Sirmione, who were then imprisoned in Verona, and there, after a two-year trial, on 13 February from 1278, more than a hundred of them were burned. In Orvieto, at the end of 1268/1269, 85 heretics were sentenced, none of whom were executed, but in 18 cases the sentence concerned people who had already died. In Tuscany, the inquisitor Ruggiero burned at least 11 people in about a year (1244/1245). Excluding the executions of the heretics at Sirmione in 1278, 36 Inquisition executions are documented in the March of Treviso between 1260 and 1308. Ten people were executed in Bologna between 1291 and 1310. In Piedmont, 22 heretics (mainly Waldensians) were burned in the years 1312–1395 out of 213 convicted. 22 Waldensians were burned in Cuneo around 1440 and another five in the Marquisate of Saluzzo in 1510. There are also fragmentary records of a good number of executions of people suspected of witchcraft in northern Italy in the 15th and early 16th centuries. Wolfgang Behringer estimates that there could have been as many as two thousand executions. This large n…

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