Eight years after his training partner LJ van Zyl claimed the gold medal in the one-lap hurdles, Fredericks did it in emphatic style in a time 48.50 seconds.
Fredericks comfortably led from the start with world champion Jehue Gordon of Trinidad and Tobago breathing down his neck.
The South African, however, kept his composure as he opened the lead to hold on to a memorable victory, with Gordon finishing second in a time of 48.75 sec and Bahaman Jeffery bagging bronze in 48.78 sec.
Gert Potgieter was the first South African to taste victory at the 1958 British Empire and Commonwealth Games in Cardiff, Wales.
South African 800m ace André Olivier ran a tactical race to claim a creditable bronze medal in the final that saw two of the greats over the two laps locking horns.
The men's 800m final lived up to expectations as it turned into a tussle between Kenya's David Rudisha, the fastest man of all time, and the third fastest, Nijel Amos of Botswana.
The Botswana athlete surged over the final 100m to claim victory in a time of 1min 45.18sec, with Rudisha taking silver in 1:45.48 and Olivier clocking 1:46.03.
There were scenes of celebrations between Amos and Olivier, who are training partners under coach Jean Verster in Potchefstroom.
South African sprinting star Akani Simbine qualified for the 200m final where he finished in fifth place, narrowly missing out on a medal with his best time of 20.37sec.
It was, however, a clean sweep of the podium for Jamaica as Rasheed Dwyer claimed gold in a time of 20.26sec.
He was followed by Warren Weir in 20.26 sec and Jason Livermore, who clocked 20.32sec.
The 20-year-old Simbine bounced back from the disappointment of narrowly missing out of a final berth in his specialist 100m sprint in which he holds the second fastest time by a South African.
South African
discus thrower Victor Hogan and women's 400m hurdles champion Wenda Nel
also featured in finals on the night but fell well short of podium
spots.
It was Team South Africa's 11th gold medal of the Games after the para-bowls triple combo of Derrick Lobban, Roger Hagerty and Dion van der Vyver won their final against New Zealand earlier in the day.
Athletics:
Women's 200m
Gold: Blessing Okagbare (NGR)
Silver: Jodie Williams (ENG)
Bronze: Bianca Williams (ENG)
Men's 800m
Gold: Nijel Amos (BOT)
Silver: David Rudisha (KEN)
Bronze: André Olivier (RSA)
Men's 400m hurdles
Gold: Cornel Fredericks (RSA)
Silver: Gordon Jehue (TRI)
Bronze: Jeffery Gibson (BAH)
Women's 400m hurdles
Gold: Kaliese Spencer (JAM)
Silver: Eilidh Child (SCO)
Bronze: Janieve Russell (JAM)
Women's long jump
Gold: Esme Brume (NGR)
Silver: Jazmin Sawyers (ENG)
Bronze: Christabel Nettey (CAN)
Men's discus
Gold: Vikas Shive Gowda (IND)
Silver: Apostolos Parellis (CYP)
Bronze: Jason Morgan (JAM)
Women's para 1500m T54
Gold: Angela Ballard (AUS)
Silver: Diane Roy (CAN)
Bronze: Jade Jones (ENG)
Men's para 1500m T54
Gold: David Weir (ENG)
Silver: Kurt Fearnley (AUS)
Bronze: Alex Dupont (CAN)
Lawn bowls
Para Open Triples
Gold: South Africa
Silver: New Zealand
Bronze: England
Women's Triples
Gold: England
Silver: Australia
Bronze: South Africa
Cycling
Women's time-trial
Gold: Linda Villumsen (NZL)
Silver: Emma Pooley (ENG)
Bronze: Katrin Garfoot (AUS)
Men's time-trial
Gold: Alex Dowsett (ENG)
Silver: Rohan Dennis (AUS)
Bronze: Geraint Thomas (WAL)
Gymnastics
Women's vault
Gold: Claudia Fragapane (ENG)
Silver: Elsabeth Black (CAN)
Bronze: Dipa Karmakar (IND)
Men's Floor
Gold: Max Whitlock (ENG)
Silver: Scott Morgan (CAN)
Bronze: David Bishop (NZL)
Men's Pommel Horse
Gold: Daniel Keatings (SCO)
Silver: Max Whitlock (ENG)
Bronze: Louis Smith (ENG)
Women's Uneven Bars
Gold: Rebecca Downie (ENG)
Silver: Larissa Miller (AUS)
Bronze: Ruby Harrold (ENG)
Men's Rings
Gold: Scott Morgan (CAN)
Silver: Kevin Lytwyn (CAN)
Bronze: Daniel Purvis (SCO)
Freestyle wrestling
Women's -55kg
Gold: Babita Kumari (IND)
Silver: Brittanee Laverdure (CAN)
Bronze: Ifeoma Nwoye (NGR) and Louisa Porogovska (ENG)
Men's -65kg
Gold: Yogeshwar Dutt (IND)
Silver: Jevon Balfour (CAN)
Bronze: Sampson Clarkson (NGR) and Alex Gladkov (SCO)
Women's -63kg
Gold: Danielle Lappage (CAN)
Silver: Geetika Jakhar (IND)
Bronze: Blessing Oborududu (NGR) and Blandine Metala Epanga (CMR)
Men's -86kg
Gold: Tamerlan Tagziev (CAN)
Silver: Andree Dick (NGR)
Bronze: Armando Hietbrink (RSA) and Pawan Kumar (IND)
Weightlifting
Men's +105kg
Gold: George Kobaladze (CAN)
Silver: Itte Detenamo (NRU)
Bronze: Damon Kelly (AUS)