The former England goalkeeper returns to the dug-out seven months after leaving Solihull Moors.
He had been in charge for a year-and-a-half when his time came to an end - and he is back in the National League with the Silkmen.
Gary Whild will act as his assistant with club legend Danny Whitaker taking on a coaching role at the Moss Rose.
Macclesfield were relegated from the EFL earlier this month after Stevenage were reprieve following an appeal.
The club return to the division they won in 2018 under John Askey.
Flowers now has the job of trying to take the club back into League Two after a difficult couple of years.
A club statement confirmed the news with signings expected soon as Town prepare for life outside the 92.
“Macclesfield Town are delighted to confirm the appointment of former Premier League winner and England goalkeeper Tim Flowers as our new First Team Manager,” it read.
“The 53-year-old will be assisted by Gary Whild and Danny Whitaker and has agreed an initial deal until the end of the 2020/21 campaign.“