In 1650, Alexis I faced two more rebellions in the cities of Pskov and Novgorod. He put down the Novgorod rebellion quickly, but was unable to subdue Pskov and was forced to promise the city amnesty in return for surrender. One man only had displayed equal tact and courage at Novgorod, Metropolitan Nikon, who in consequence became in 1651 the tsar's chief minister. On 1 August 1652 he was elected Patriarch of Moscow, however, Nikon knew that he was rather unpopular with the Russian nobility and declined the offer several times. He gave in after the tsar himself and the boyars fell on their knees, begging him to accept the post. He only yielded after imposing upon the whole assembly a solemn oath of obedience to him in everything concerning the dogmas and canons of the Orthodox Church. He preached that the Orthodox mission of the Russian tsar must be purified, ready for a crusade against the Catholic Poles and Islamic Tatars.

On 1 October 1653 the National Assembly met at Moscow to sanction the war against Poland and find the means of carrying it out and in April 1654 the army was blessed by Patriarch Nikon. On 18 May 1654, accompanied by Morozov and his father-in-law, Ilya Miloslavsky, Alexis I, just twenty-five years old, led his army out of Moscow towards Smolensk. The campaign of 1654 was an uninterrupted triumph and towns, including the important fortress of Smolensk, fell into the hands of the Russians. Russia not only recovered Smolensk but also occupied all of what is now eastern Ukraine, Belarus and even took the traditional Lithuanian capital Vilnius. In the summer of 1655, the sudden invasion by Charles X of Sweden for the moment swept the Polish state out of existence, in what became known as the Deluge. The Russians, unopposed, quickly appropriated nearly everything which was not already occupied by the Swedes and, when at last the Poles offered to negotiate, the grand duchy of Lithuania was the least of the demands of Alexis I. Fortunately for Poland, the tsar and the Swedish king now quarrelled over the apportionment of the spoils and at the end of May 1656 Alexis I, encouraged by Holy Emperor Ferdinand III and the other enemies of Sweden, declared war. In the meantime Poland had so far recovered herself as to become a more dangerous foe than Sweden and, as it was impossible to wage war with both simultaneously, Alexis I resolved to rid himself of the Swedes first, which he did by the Peace of Kardis on 2 July 1661, whereby Russia retroceded all her conquests.

Meanwhile, Nikon made it his mission to remove the church from secular authority and permanently separate the church from the state. He also sought to organize the church with a hierarchy similar to the state's - with the patriarch in complete control. The priest and the young autocrat openly clashed during a service. In the result, Alexis I ceased to consult him, half revering, half lothing the man. On 4 July 1658, Alexis I did not invite the patriarch to a banquet for the visiting Georgian king Teimurz I. Almost as a test of wills and, perhaps, hoping to dramatize his own importance, Nikon publicly stripped himself of his patriarchal vestments in the summer 1658 and went to live at the New Jerusalem Monastery, that he, himself, founded in the town of Istra. For many years the tsar and Nikon remained estranged and their conflict unresolved.

By the 1660s, Alexis I's wars with Poland and Sweden had put an increasing strain on the Russian economy - his government had begun minting copper coins in an attempt to increase government revenue, but this instead led to a devaluation of the ruble and a severe financial crisis. As a result, angry Moscow residents revolted in the 1662 Copper Riot, which was put down violently. Up to thousand men were hanged or drowned in the Moscow River. Several thousand people were arrested and later exiled after the brutal investigation. The Salt Riot shook the tsar, who suffered palpitations, nosebleeds and indigestion which his doctors treated with laxatives, opium and hellebore to slow the heart down.

In December 1666, Nikon was tried by a synod of church officials, known as the Great Moscow Synod. During the proceedings, Nikon staunchly defended his belief that the church's authority and power were and ought to be supreme. On 12 December the synod, pronounced him guilty of reviling the tsar and the Orthodox Church and of beating and torturing his dependents. His sentence was deprivation of all his sacredotal functions; henceforth he was to be known simply as the monk Nikon. The same day he was put into a sledge and sent as a prisoner to the far northern Ferapontov Monastery. Yet the very council which had deposed him confirmed all his reforms and anathematized all who should refuse to accept them. Nikon survived Alexis I with whom something of the old intimacy had been resumed in 1671. In 1681 Tsar Fedor III, on hearing that Nikon was dying, allowed him to return to Moscow and, under a partial pardon, take up residence in his former Moscow home, the New Jerusalem Monastery. Unfortunately at Yaroslavl on his way there, after crossing the Kotorosl River, he died in Tropino on 17 August 1681.

In the meantime, the Polish were handicapped by internal dissent and the outbreak of a civil war between the various noble factions. It was due to Afanasy Ordin-Nashchokin's abilities and his tenacity of purpose that Russia succeeded in concluding with Poland the advantageous Truce of Andrusovo on 11 February 1667. On his return to Russia he was created a boyar and entrusted with the direction of the Foreign Office, with the title of Guardian of the Great Tsarish Seal and Director of the Great Imperial Offices. He was, in fact, the first Russian chancellor. According to the truce, Polotsk and Polish Livonia were restored to Poland, but the more important Smolensk and Kiev remained in the hands of Russia together with the whole eastern bank of the Dnieper River.

The year of 1667 was undoubtedly one of triumph for Alexis I. Not only had he defeated the Polish enemies who had held Russia in check for two centuries, but he also showed who was in charge in the Orthodox Church. Indeed, he felt confident enough to impose higher tariffs on Western European import and export trade with Russia and made a move to intensify economic ties with Safavid Iran. This was potentially lucrative, as the Persians were a key source for raw silk that was in high demand at that time in Western Europe. Alexis I's atempts to reroute this trade away from the overland caravan route that ended at Turkish held Mediterranean ports did not succeed in the end because he was confronted with Stepan (Stenka) Razin rebellion in 1670-1671.

A long war with Poland in 1654-1667 and Sweden in 1656-1658 put heavy demands upon the people of Russia. Many peasants, hoping to escape the burdens, fled south and joined bands of Razin's marauding Cossacks. They were also joined by many others who were disaffected with the Russian government, including people of the lower classes, as well as representatives of non-Russian ethnic groups such as the Kalmyks, that were being oppressed at the time. Razin's first considerable exploit was to destroy the great naval convoy consisting of the treasury barges of the rich merchants of Moscow. Razin then sailed down the Volga, capturing the more important forts on his way and devastating the country. At the beginning of 1668, he defeated Yakov Bezobrazov, sent against him from Astrakhan, and in the spring embarked on a predatory expedition into Daghestan and Persia, which lasted for eighteen months.

On 24 June 1670 Razin reached Astrakhan, which occupied a strategically important location at the mouth of the Volga River on the shore of the Caspian Sea. He plundered the city despite its location on a strongly fortified island and the stone walls and brass cannons that surrounded the central citadel. After massacring all who opposed him and giving the rich bazaars of the city over to pillage, he converted Astrakhan into a Cossack republic, dividing the population into thousands, hundreds and tens, with their proper officers, all of whom were appointed by a general assembly and whose first act was to proclaim Stepan Razin their sovereign.

After a three-weeks carnival of blood and debauchery Razin quit Astrakhan with two hundred barges full of troops. His aim was to establish the Cossack republic along the whole Volga River as a preliminary step towards advancing against Moscow. Saratov and Samara were captured, but Simbirsk defied all efforts and after two bloody battles on the banks of the Svyaga River, Razin was routed by the army of Yuri Baryatinsky and fled down the Volga River, leaving the bulk of his followers to be extirpated by the victors. At Simbirsk Razin's prestige had been shattered. Even his own settlements at Saratov and Samara refused to open their gates to him and the Cossacks, hearing that the patriarch of Moscow had anathematized Razin, also declared against him.