Teams in the Bundesliga have been able to make up to five changes, instead of the usual three, in a decision approved by FIFA's International Board with the aim of keeping players fresh and avoiding additional injuries after the lengthy break due to coronavirus.
LaLiga will adopt the same measure and while in theory it appears the bigger teams will benefit, Setien sees it differently in Barca's case.
"I don't know if it will harm us or benefit us," the 61-year-old told the Las Palmas Football Federation in an interview. "I think it will harm us because of our way of playing.
"We know that a lot of matches we will resolve in the final minutes. If you give the rival the option of putting on fresh players in that time, the weakness that is generated, with tired players, won't come about.
"But it can also give you resources in a specific moment. It's an unknown quantity and we'll see how it goes."
Setien also revealed he would have liked more time to prepare for the restart, which is scheduled for June 11, with only 10 days of training all together ahead of the big kick-off.
"We thought we would have more time to work as a group, but it's not to be," he said. "We would have liked more time. I hope there are not many injuries and that it's less harmful than we imagine."
On a positive note, the former Real Betis coach claimed his players were raring to go after the break.
"The players are mentally rested," he said. "Now they are keen to get back on the pitch. Having not played for so long is a motivation in itself."
Barca are two points ahead of Real Madrid at the top of LaLiga with 11 rounds of fixtures remaining.
"It's clear that we will start to compete with a high level of stress because you are playing for LaLiga in 11 games," Setien said.
"That, together with the physical effort, we don't know how it will affect us. We will see as time goes by."