The Australia striker, who was rested for the Champions League clash with Benfica in Lisbon on Wednesday, looked sharp against his former club, scoring the opener three minutes before the interval with a close-range header.
His strike just before the hour mark and an 87th-minute penalty wrapped up the points for the champions who moved three points clear of rivals Rangers.
It was McDonald's second hat-trick since signing from the Lanarkshire side in the summer, the other coming against Dundee United at home last month.
And he showed his value to Gordon Strachan's side again with a master class in finishing, spoiled only by a first-half booking for diving.
The visitors started with intent. Mark McGhee's men took less than 30 seconds to win their first corner from which they mounted a spell of pressure which included Chris Porter heading high over the bar and Steven McGarry driving over from distance before Ross McCormack drew a fine save from Artur Boruc with a powerful drive.
The Fir Park side had to reshuffle in the 10th minute as Phil O'Donnell replaced the injured Stephen Hughes.
But two minutes later, Celtic had their first effort on goal when Chris Killen's drive from 16 yards, after he had picked up a Shunsuke Nakamura pass, was blocked by Motherwell keeper Graeme Smith.
At the other end, Smith made a magnificent point-blank save from a Killen header following a Nakamura corner.
As Celtic began to take control, midfielder Paul Hartley raced on to a reverse pass from Nakamura but his shot from 12 yards was again blocked by the on-rushing Smith.
Motherwell had lost most of their earlier threat but just before the half-hour mark, McCormack fizzed a left-footed drive from 25 yards just past Boruc's left-hand post after Paul Quinn's cut-back had caused panic in the Parkhead defence.
There was more concern in the 36th minute when Boruc's throw to Lee Naylor was too strong for the Celtic defender.
The alert McGarry nipped in and his attempted lob from the edge of the box was pushed over the bar by the Poland international. At the other end, Smith again showed his form by making a fine save down at his left side from Scott Brown before Motherwell skipper Stephen Craigan headed a McCormack corner over the bar.
McDonald was booked in the 40th minute by referee Stuart Dougal for diving in the Motherwell penalty area but two minutes later he grabbed the opener against his former side.
A Nakamura corner from the left came in to a packed six-yard box and was headed in by the Australian international.
Seconds before the interval, with the Fir Park defence in disarray, Craigan cracked the ball against his own post preventing Killen scoring number two.
McDonald had a weak header across goal and then a mis-kick from 14 yards out within two minutes of the restart but Celtic were clearly in control.
Then, in the 51st minute, Aiden McGeady curled a wonderful shot from 20 yards which beat Smith but crashed off the crossbar.
Porter escaped the attention of Celtic skipper McManus on the touchline and galloped clear but the former Oldham striker's cut-back was easily saved by Boruc at his near post.
Porter had a great chance in the 56th minute when he ran on to a McCormack pass that had split the Celtic rearguard but once again Boruc was equal to the low drive. The miss quickly proved costly for, in the 59th minute, the points were secure when McDonald grabbed number two.
A delightful Naylor pass into the left channel left the former Fir Park striker with only Smith to beat and he drilled his shot under the Motherwell keeper.
Motherwell continued to go forward but the gaps they left offered Celtic the chance to increase their lead, McGeady driving past from the edge of the box on one such occasion.
In the 83rd minute Nakamura slipped when he only had Smith to beat from 10 yards out and the ball went high and wide.
McDonald, however, was not finished. With three minutes remaining, Craigan fouled him in the penalty area and the Celtic striker slotted the spot-kick away for his second hat-trick of his Parkhead career to take the champions clear at the top of the table.
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