Weir, who won 5000m - T54 gold on Sunday, successfully defended his 1500m -T54 title, hitting the front with around 300m to go before holding off his rivals down the home straight to deafening cheers.
He crossed the line in 3:12.09, producing a 44.84 last lap to finish 0.23 ahead of Thailand's Prawat Wahoram.
'It's just an amazing feeling as it is the blue riband event,' Weir said. 'Every wheelchair racer wants to win the 1500m. I've done it twice now, so it's a great honour. I always dreamt of winning them and I've done it twice.'
Australian swimmer Jacqueline Freney won her sixth gold of London 2012 as Natalie du Toit moved closer to her impending retirement with yet another Paralympic title at the Aquatics Centre.
Freney won the 50m Freestyle - S7 in a Paralympic record of 32.63 to add to the five golds she had already claimed.
South African Du Toit came into the Games with 10 Paralympic titles and one silver. Tonight's victory in the 400m Freestyle - S9 was her second of the meet along with the 100m Butterfly - S9.
Belarusian Ihar Boki claimed his fourth gold medal and fifth overall when he demolished his own world record in the 400m Freestyle - S13, finishing in 3:58.78.
Justin Zook lowered the 100m Backstroke - S10 world record - especially impressive given he was reclassified ahead of the competition. The USA swimmer dipped 0.54 inside Andre Brasil's mark in 1:00.01.
At Greenwich Park, gold went to Belgium's Michele George and Rainman in the Individual Freestyle Test - Grade IV Equestrian final. Britain's Sophie Wells was second and Frank Hosmar of Holland third.
Sophie Christiansen became London 2012's first British triple gold medallist today with Individual Freestyle - Grade Ia gold on Janeiro 6. Laurentia Tan of Singapore was second and Helen Kearney of Ireland third.
Hannelore Brenner of Germany won Individual Freestyle - Grade III gold on Women of the World ahead of Deb Criddle of Britain and Annika Dalskov of Denmark.
British archer Danielle Brown successfully defended her women's Individual Compound - Standing competition title at the Royal Artillery Barracks in a tense final with team-mate Mel Clarke. Stepanida Artakhinova won bronze with a 7-3 defeat of fellow Russian Marina Lyzhnikova.
Iran's Zahra Nemati won the women's Individual Recurve - W1/W2 gold medal with a 7-3 win over Elisabetta Mijno of Italy.
In the women's Individual Recurve - Standing final, China's Yan Huilian claimed a 6-4 win over South Korea's Lee Hwa Sook.
Loveline Obiji became the fourth Nigerian woman to claim Powerlifting gold, with victory in the -82.5kg competition at ExCeL. Obiji lifted 145kg with her opening attempt to finish ahead of silver medallist Randa Mahmoud of Egypt. China's Yanmei Xu was third.
In the corresponding men's event, Iran's Majid Farzin took gold with a best of 237kg, with China's Xiao Fei Gu taking silver with 228kg and world champion Metwaly Mathana of Egypt bronze in 227kg.
Egypt's Hany Abdelhady won the men's -90kg title in a Paralympic record of 241kg. China's Cai Huichao took silver (233kg) and Pavlos Mamalos of Greece (232kg) bronze.
In Boccia, Greece won the Mixed Pairs - BC3 ahead of Portugal and Belgium. Brazil won the Mixed Pairs - BC4 title ahead of Czech Republic and Canada, while the Mixed Team - BC1-2 crown was claimed by Thailand ahead of China and Britain.
Abdulla Sultan Alaryani won gold for the United Arab Emirates in the Mixed R6-50m Rifle Prone - SH1 Shooting final, beating Reinaldo Saavedra of Spain and Matthew Skelhon of Britain.