The Yorkshire batsman was the biggest casualty as England named their squad for the games in the United Arab Emirates starting next month.
Lyth was axed after scoring 115 runs in the five Tests against Australia, while county colleague Gary Ballance was also overlooked.
Yorkshire players still make up one-quarter of the 16-man squad, with Joe Root, Jonny Bairstow, Adil Rashid and Liam Plunkett all chosen.
Root and Rashid are also in separate 15-man one-day and T20 squads, with Bairstow also in the one-day squad.
Nottinghamshire batsman Alex Hales is in line to replace Lyth, while Surrey left-arm spinner Zafar Ansari is the third spinner behind Moeen Ali and Rashid.
National selector James Whitaker said: “Alex Hales has scored heavily for Nottinghamshire in first-class cricket this season, has shown he can play match-winning innings for England in white-ball cricket, and fully deserves an opportunity to compete for a place at the top of the order in our Test side.
“The challenge we face against Pakistan will be very different, and the composition of our squads reflects the conditions we expect to encounter in the UAE.
“Zafar Ansari’s potential excites us, and he will provide strong competition for Adil Rashid and Moeen Ali in the Test squad after enjoying an excellent domestic season.”
England have chosen to rest Ben Stokes for the four ODIs and three T20s that follow the three-Test series.
Whitaker explained: “In line with our recent decision to rest Joe Root for the one-day series against Australia, we have opted not to include Ben Stokes in our one-day or T20 international squads.
“Ben has been an outstanding performer for England this summer, and this decision reflects a desire to manage his workload across a busy winter period in all three formats of the game.
“He will come back into contention for the white-ball format when we consider the make-up of our squads for the tour of South Africa later in the year.”
Paul Collingwood and Mahela Jayawardene are to join the England team this winter in consultancy roles.