On May 1, 2018, three weeks after the 2017–18 Buffalo Sabres season ended, team president Russ Brandon announced his resignation from Pegula Sports and Entertainment. In a statement to the press, Brandon stated that the departure had been planned since he had reached 20 years with the Bills in November 2017 and that he fulfilled his duties to the Bills and Sabres for the remainder of the Sabres' season before tendering his resignation. A report in The Buffalo News claimed that Brandon had been subject to an internal investigation regarding inappropriate relationships with female employees; neither the Bills, Sabres nor Brandon mentioned such in their statements.
The Bills traded their first- and second-round selections (12th, 53rd and 56th overall) to the Tampa Bay Buccaneers in exchange for Tampa Bay's first- and seventh-round selections (7th and 255th overall).
The Bills traded their first- and third-round selections (22nd and 65th overall) to the Baltimore Ravens in exchange for Baltimore's first- and fifth-round selections (16th and 154th overall)
The Bills traded their first- and fifth-round selections (21st and 158th overall) and offensive tackle Cordy Glenn to the Cincinnati Bengals in exchange for Cincinnati's first- and sixth-round selections (12th and 187th overall).
The Bills traded their first-round selection in 2017 (10th overall) to the Kansas City Chiefs in exchange for Kansas City's first-round selection (22nd overall) as well as their first- and third-round selections in 2017 (27th and 91st overall).
The Bills traded their sixth-round selection (195th overall) and wide receiver Sammy Watkins to the Los Angeles Rams in exchange for the Rams' second-round selection (56th overall) and cornerback E.J. Gaines.
The Bills traded quarterback Tyrod Taylor to the Cleveland Browns in exchange for Cleveland's third-round selection (65th).
The Bills traded their third-round selection (85th overall), quarterback Cardale Jones and the seventh-round selection they acquired from the Los Angeles Chargers (234th overall) to the Carolina Panthers in exchange for wide receiver Kelvin Benjamin.
The Bills traded cornerback Ronald Darby to the Philadelphia Eagles in exchange for Philadelphia's third-round selection (96th overall) and wide receiver Jordan Matthews.
The Bills traded defensive tackle Marcell Dareus to the Jacksonville Jaguars in exchange for a conditional sixth-round selection, which became a fifth-round selection (166th overall) after Dareus remained on Jacksonville's roster for the remainder of the 2017 season and the Jaguars made the playoffs.
The Bills traded their seventh-round selection (239th overall) to the Green Bay Packers in exchange for linebacker Lerentee McCray.
The Bills' preseason opponents and schedule was announced on April 11, 2018. For the first time since at least 2005, the Detroit Lions, who the Bills will play in Week 15, are not included on the preseason schedule.
Networks and times from Weeks 5 to 17 are subject to change as a result of flexible scheduling with the exception of Week 8 (Monday Night Football).
The broadcast simulcast partner for the ESPN game has not yet been determined. WKBW-TV, which previously held the rights, had its contract expire after the 2017 season, but may have a right of first refusal clause. WGRZ and WUTV have both expressed intent on bidding on the game; WBBZ-TV, which most recently simulcast cable games before WKBW's contract, has not made its intentions clear (the consensus is that the station, whose sports director left the station in 2015, is no longer willing to pay the rights fee for sports broadcasts such as the NFL), nor has WIVB-TV, which does not publicly state its future programming intentions under corporate policy.