Down's Martin Clarke gets a shot away despite Ronan McGarrity's best efforts
Down had to settle for a draw in the Allianz Football League Division 1 opener in Castlebar after leading for nearly all of the contest.
A Martin Clarke '45 went straight into the net early on and his brother John lashed in another first-half goal after great work by Benny Coulter.
Alan Freeman's deflected goal cut Down's lead to 2-5 to 1-4 at half-time.
Peter Fitzpatrick's goal put Down five up but Andy Moran brought his tally up to six points as Mayo fought back.
The 2010 All-Ireland finalists were without injured Dan McCartan, Kevin Duffin, Conor Garvey, Declan Rooney and Damien Rafferty and Liam Doyle was also a late withdrawal from the contest.
However, the Mourne men got off to the perfect start as Clarke's 45 beat Mayo keeper O'Malley in the second minute.
John Clarke stroked in Down's second goal in the 20th minute and added a further immediate point to extend the lead to 2-4 to 0-3.
Mayo were back in the contest in the 25th minute as Freeman's shot deflected off a Down defender and past Brendan McVeigh.
After leading 2-5 to 1-4 at half-time, Martin Clarke extended Down's lead but Mayo responded with four unanswered scores - including a couple of Mark Ronaldson efforts.
Down appeared in control again when Benny Coulter set up Peter Fitzpatrick to lash in their third goal.
But Mayo weren't finished as Moran (two), Freeman and Kevin O'Loughlin struck unanswered points to level proceedings with five minutes remaining.
Substitute Conor Maginn edged Down ahead again but Moran's sixth and final point restored parity once again.
Both Martin Clarke and Mayo's Peadar Gardiner missed late chances to win it but a draw was probably a fair result.