After Nagayoshi died, he supported the young head of the family, Yoshitsugu MIYOSHI allied with other Miyoshi sanninshu and Hisahide MATSUNAGA, and ultimately assassinated Yoshiteru ASHIKAGA in 1565 (the Eiroku no Hen) (Conspiracy of Eiroku).
長慶の死後は幼少の当主・三好義継を他の三人衆や松永久秀らと共に補佐し、永禄8年（1565年）にはついに足利義輝を暗殺した（永禄の変）。