Afridi, 35, who has played 354 ODIs since debuting in 1996, has only struck two half-centuries in his last 15 matches.
The big-hitting leg-spinner has not taken a wicket in his last six one-day internationals and it is his poor form with the ball that has resulted in his omission.
"Afridi's bowling has not been up to the mark in recent matches," said chief selector Iqbal Qasim.
"He has not taken wickets and his primary role in the team is that of a bowler."
This summer's tournament begins on June 6.
Pakistan squad for ICC Champions Trophy: Nasir Jamshed, Imran Farhat, Mohammad Hafeez, Asad Shafiq, Misbah-ul-Haq, Shoaib Malik, Umar Amin, Kamran Akmal, Saeed Ajmal, Abdul Rehman, Junaid Khan, Mohammad Irfan, Asad Ali, Ehsan Adil, Wahab Riaz