A five-match winning run had been halted by three games without a victory in recent weeks, but the early signs were promising for Werder as Jannik Vestergaard headed just wide from a free kick.
Di Santo brought a fairly uneventful first half to life 10 minutes before the break as he used space on the edge of the box to curl home an unstoppable strike.
Freiburg had the chance to get back on level terms just before the interval, but Admir Mehmedi was left frustrated as his strike drifted just over the crossbar.
Werder appeared to happy to operate on the counter-attack in the second half, and they were inches away from doubling their lead when Zlatko Junuzovic fired wide from outside the box.
The hosts enjoyed enough possession to suggest that they could find an equaliser, but Christian Streich's side wasted their rare opportunities, with Marc-Oliver Kempf failing to convert with a free header from Jonathan Schmid's corner.
Werder defended impressively in the closing stages to hold onto their slender advantage as Freiburg missed the chance to climb out of the relegation zone.