After installing Yoshiaki as shogun, Nobunaga had evidently pressed Yoshiaki to request all the local daimyos to come to Kyôto and attend a certain banquet. Asakura Yoshikage, head of the Asakura clan was the regent of Ashikaga Yoshiaki, refused, an act Nobunaga declared disloyal to both the shogun and the emperor. With this pretext well in hand, Nobunaga raised an army and marched on Echizen. In early 1570, Nobunaga launched a campaign into the Asakura clan's domain and besieged Kanagasaki Castle. Azai Nagamasa, to whom Nobunaga's sister Oichi was married, broke the alliance with the Oda clan to honor the Azai-Asakura alliance, which had lasted for generations. With the help of the Rokkaku clan and the Ikkō-ikki, the anti-Nobunaga alliance sprang into full force, taking a heavy toll on the Oda clan. Nobunaga found himself facing both the Asakura and Azai forces and when defeat looked certain, Nobunaga decided to retreat from Kanagasaki, which went successfully. In July 1570, the Oda-Tokugawa allies marched on Yokoyama and Odani Castles, and the combined Azai-Asakura force marched out to confront Nobunaga. Nobunaga advanced to the southern bank of the Anegawa. The following morning, on 30 July, 1570, the battle between the Oda and the Azai-Asakura forces began. Tokugawa Ieyasu joined his forces with Nobunaga, with the Oda and Azai clashing on the right while Tokugawa and Asakura grappled on the left. The battle turned into a melee fought in the middle of the shallow Ane River. For a time, Nobunaga's forces fought the Azai upstream, while the Tokugawa warriors fought the Asakura downstream. After the Tokugawa forces finished off the Asakura, they turned and hit the Azai right flank. The troops of the Mino Triumvirate, who had been held in reserve, then came forward and hit the Azai left flank. Soon both the Oda and Tokugawa forces defeated the combined forces of the Asakura and Azai clans. This battle would go on to be known as the Battle of Anegawa.
Nobunaga faced a significant threat from the Ikkō-ikki, a resistance movement centered around the Jōdo Shinshū section of Buddhism. The Ikkō-ikki began as a cult association for self-defence, but popular antipathy against the samurai from the constant violence of the Sengoku period caused their numbers to swell. By the time of Nobunaga's rise to power, the Ikkō-ikki was a major organized armed force opposed to samurai rule in Japan. In August 1570, Nobunaga launched the Ishiyama Hongan-ji War against the Ikkō-ikki, while simultaneously fighting against his samurai rivals. In May 1571, Nobunaga besieged Nagashima, a series of Ikkō-ikki fortifications in Owari Province, beginning the Sieges of Nagashima. Nobunaga's first siege of Nagashima ended in failure, as his trusted general Shibata Katsuie was severely wounded and many of his samurai were lost before retreating. Despite this defeat, Nobunaga was inspired to launch another siege, after the success of the Siege of Mount Hiei. In July 1573, Nobunaga besieged Nagashima for a second time, personally leading a sizable force with many arquebusiers. However, a rainstorm rendered his arquebuses inoperable while the Ikkō-ikki's own arquebusiers could fire from covered positions. Nobunaga himself was almost killed and forced to retreat, with the second siege being considered his greatest defeat. In 1574, Nobunaga launched a third siege of Nagashima as his general Kuki Yoshitaka began a naval blockade and bombardment of Nagashima, allowing him to capture the outer forts of Nakae and Yanagashima as well as part of the Nagashima complex. The Sieges of Nagashima finally ended when Nobunaga's men completely surrounded the complex and set fire to it, killing the remaining tens of thousands of defenders and inflicting tremendous losses to the Ikkō-ikki.
One of the strongest rulers in the anti-Nobunaga alliance was Takeda Shingen, who used to be an ally of the Oda clan. At the apex of the anti-Nobunaga coalition, in 1572, Takeda Shingen ordered Akiyama Nobutomo, one of the "Twenty-Four Generals" of Shingen, to Siege on Iwamura castle. Nobunaga's aunt, Lady Otsuya, conspired against the Oda clan, surrendered the castle to the Takeda and married Nobutomo. From there, the Takeda-Oda relationship declined and Nobunaga started a campaign against the Takeda clan. In the same year, Shingen decided to make a drive for Kyoto at the urgings of the shogun Ashikaga Yoshiaki, starting with invading Tokugawa territory. Nobunaga, tied down on the western front, sent lackluster aid to Tokugawa Ieyasu who suffered defeat at the Battle of Mikatagahara in 1573. However, after the battle, Tokugawa's forces launched night raids and convinced Takeda of an imminent counter-attack, thus saving the vulnerable Tokugawa with the bluff. This would play a pivotal role in Tokugawa's philosophy of strategic patience in his campaigns with Nobunaga. Shortly thereafter, the Takeda forces were neutralized after Shingen died in April of 1573.
After the death of Takeda Shingen, Nobunaga's entry into Kyôto presented him with a situation very different from that from which he had come. He focused on Ashikaga Yoshiaki, who had openly declared hostility more than once, despite the Imperial Court's intervention. Nobunaga was able to defeat Yoshiaki's forces, and the power of the Ashikaga was effectively destroyed on 27 August, 1573, when Nobunaga drove Yoshiaki out of Kyoto and sent him into exile. After the Ashikaga Shogunate came to end, the authority of the Imperial Court of Emperor Ōgimachi also began to fall. This trend reversed after Oda Nobunaga entered Kyoto in a show of allegiance that indicated that the Emperor had the Oda clan's support. In early 1574, Nobunaga was promoted to the Lower Third Rank (Ju Sanmi) of the Imperial Court and made a Court Advisor (Sangi). Court appointments would continue to be lavished on a nearly annual basis, possibly in hope of placating him. Nobunaga acquired many official titles, including Major Counselor (Gondainagon), Ukon'etaishō, and Minister of the Right (Udaijin) in 1576. In February 1578 the court made him Grand Minister of State (Daijo daijin), the highest post that could be given. By 1580, Nobunaga was the most powerful lord in Japan, controlling 20 provinces in central Japan: Owari, Mino, Omi, Iga, Ise, Yamato, Yamashiro, Kawachi, Izumi, Settsu, Echizen, Hida, Kaga, Shinano, Kai, Tango, Harima, Inaba, Tanba and Bizen.