Freddie Heldreich and Max Hunt both took four wickets but Glamorgan found themselves in pole position heading into the last day at Campbell Park.
Glamorgan started the penultimate day 35/0 and continued their strong start, putting on a 94-run partnership before Macgregor fell to Bailey Wightman just 6 runs short of his half century.
The next over saw Academy off spinner Max Hunt remove Callum Nicholls first ball, as Hunt got one to spin past the bat to knock back off stump.
Hunt picked up his second wicket six overs later, trapping opener Joseph Fielding LBW for 56 as Glamorgan 2XI found themselves 110/3.
Tribe and Smale put together a 73 run partnership before Heldreich bowled Smale as he tried to sweep the leg spinner. Another wicket fell in the next over as Hunt took his third, bowling Naish for 2 through the gap between bat and pad.
Heldreich took three wickets and Hunt took another as the 2XI bowled Glamorgan 2XI all out for 318, leaving Northamptonshire requiring a target of 451 in their second innings.
Heldreich finished with figures of 4/84 from 13.4 overs, while Hunt ended 4/101 off 26 overs with an economy rate of 3.88.
George Hargrave opened the batting for the 2XI with Hassan Azad, who returned from his involvement in the One Day Cup in Cardiff on Tuesday.
The left hander only managed to put on 11 before cutting one straight to Hope-Bell at point.
Hughes-Rowlands was in at three but fell in the next over, catching a top edge from James Harris to give the seamer a simple caught and bowled.
Nico Reifer also fell shortly after for 15, giving Hope-Bell his second catch of the innings as he pulled one straight to the fielder at square leg, leaving the 2XI 54/3.
Josh Cobb and Hargrave rebuilt the innings for the 2XI, putting on an 85 run partnership before the end of play. The pair guided the side to 139/3 by the end of the day, with Cobb on 37 and Hargrave on 64.