[13] On March 26, 2015, O'Connor enjoined the federal government's definition of marriage as it relates to the Family and Medical Leave Act of 1993.

The guidance from the White House was issued in May 2016, and addresses the Title IX requirement that schools receiving federal funding not discriminate against students on the basis of sex.

O'Connor ruled that the new guidelines did not receive proper notice and comment prior to publication, and that Title IX and its implementing regulation are "not ambiguous" as to the "plain meaning of the term sex as used".

[17][18] On December 31, 2016, in a separate case, O'Connor issued a preliminary injunction against enforcement of the Obama administration's regulations implementing Section 1557 of the Affordable Care Act (prohibiting sex discrimination in federally funded health programs) as a likely violation of the Religious Freedom Restoration Act and what he said was an improper inclusion of gender identity discrimination.

[19] In early 2018, O'Connor held the Certification Rule of the Affordable Care Act unconstitutional in Texas v. Commissioner of Internal Revenue, finding it violated the nondelegation doctrine.

[27] In October 2022, O'Connor ruled that the Boeing Company committed criminal acts when not disclosing the MCAS system of the FAA.

This contradicted the previous settlement the federal government made with Boeing, and opened the door for new legal action by victims families.

[31][32] In an act criticized as an example of forum shopping, Elon Musk's website X (Twitter) filed two lawsuits in O'Connor's court division although neither it nor the defendants are located in Texas.

[33] Judge O'Connor drew additional scrutiny after published reports revealed that he owned stock in Tesla, another company run by Musk.

"[36][38] This is in reference to National Federation of Independent Business v. Sebelius (2012) which ruled that the individual mandate was constitutional because of the tax penalty.

"[40] Jonathan H. Adler and Abbe R. Gluck, who were on opposing sides of the 2012 and 2015 Supreme Court challenges to the Affordable Care Act, wrote a joint opinion editorial in The New York Times where they described the ruling as "lawless", "a mockery of the rule of law and basic principles of democracy" and "an exercise of raw judicial power.

al., on March 30, 2023, O'Connor sided with conservative employers and individuals in Texas who argued that the Affordable Care Act's provision mandating that businesses provide their employees with free coverage of preventative services including mammograms, colonoscopies, mental health screenings, and the HIV prevention drug PrEP was unconstitutional.

[51] He also wrote that the coverage requirements violate employers' religious beliefs "by making them complicit in facilitating homosexual behavior, drug use, and sexual activity outside of marriage between one man and one woman.