Jokanovic signed a three-year deal to take over at Bramall Lane following the Blades' relegation to the Championship, but has departed only six months into his reign with the club 16th in the second tier.
Heckingbottom, who stepped in as caretaker boss last season following Chris Wilder's departure, has been installed as boss on a long-term deal.
The former Leeds United, Barnsley and Hibernian manager had been in charge of the South Yorkshire club's Under-23 side. Stuart McCall will be Heckingbottom's number two.
"Sunday's game & this season is most important. I believe in the players & I know that we should and could be up there but it's going to take a hell of a lot of work.— Sheffield United (@SheffieldUnited) November 25, 2021
No excuses, if we want to get there we have to go and earn it. We have to go and attack it." - Hecky.#SUFC 🔴 pic.twitter.com/NvQk33bnSy
The Blades were relegated from the Premier League with a whimper last season, finishing bottom after winning only seven matches.