Sykes won election to a newly created trial judge seat on the Milwaukee County Circuit Court in 1992, serving in the misdemeanor, felony, and civil divisions.

[4][11] On June 7, 2017, Rep. Louie Gohmert of Texas's 1st congressional district commented on her conservative judicial philosophy: "There are only two reliable originalists on the Seventh Circuit, Michael Kanne and Diane Sykes.

[17] In April 2017, Sykes dissented when the en banc Seventh Circuit, by a vote of 8–3, found that LGBT Americans were protected from sex discrimination by Title VII of the Civil Rights Act of 1964.

[18] In her dissent, Sykes argued the court should have applied a "textualist decision method" instead of the majority's "sex stereotyping" reasoning or the "judicial interpretive updating" Judge Richard Posner promoted in his concurrence.

[19] In April 2018, Sykes wrote for a unanimous court when it found that the Americans with Disabilities Act did not require an employer to grant a multi-month leave of absence as a reasonable accommodation.

[22] In July 2018, Sykes wrote for a unanimous panel when it found that a new Illinois law that required previously convicted sex offenders to relocate their residences away from newly opened daycares did not violate the Constitution's Ex Post Facto Clause.