Resuming on 56-4 chasing a target of 273, O'Brien and Aadil Ali extended their fifth-wicket stand to 138 before O'Brien was lbw to Mark Footitt for 87.
Ali (42) shared a fifty partnership with Andrea Agathangelou but both fell quickly to leave the hosts 238-7.
However, Ben Raine's 31 not out off 37 balls saw the Foxes to 273-7 and their second Division Two win of the season.
"An early tea is being taken at Lord's after a sharp shower brought the players off with Sussex 142-5 having been set 266 to win.
"Chris Nash is leading the way with an unbeaten fifty after James Harris picked up three wickets to slow a rapid start to the chase.
"No further interruptions are expected and a result looks certain either way so Middlesex will hope for quick wickets on a pitch offering assistance to check the visitors' progress."
Hampshire's survival fight was given a boost as they sealed a 216-run win over second-placed Warwickshire, whose own title ambitions took a setback.
The Bears resumed on 161-6 at the Ageas Bowl - still 283 runs off their target of 444 - and lost Rikki Clarke (55) to Jackson Bird's fourth ball of the day.
Fidel Edwards (4-55) took two more wickets to end with match figures of 9-87 as the visitors were out for 227.
Lunch: Notts close in on victory at New Road
Worcestershire 269 & 292, Notts 330 & 188-3
Only 45 minutes of play were possible in the morning session because of rain, but there was still time for Nottinghamshire to move within 44 runs of victory against Worcestershire.
Riki Wessels is unbeaten on 85 and James Taylor is 63 not out.
The pair have shared a fourth-wicket stand of 151 and look set to take Notts to their fourth Championship win of the summer.
Lunch: Second Foxes win on the cards
Derbyshire 345 & 241, Leicestershire 142-4
Niall O'Brien and Aadil Ali have put on 92 for the fifth wicket to keep Leicestershire's hopes of a second victory of the summer alive against Derbyshire.
The Foxes are 142-4 at lunch, needing 130 more runs for victory.
"All bubbling up nicely at Colchester. Essex declared after an hour's play after Gareth Batty's five wickets leaving a victory target of 313 for Surrey.
"Rory Burns and Zafar Ansari made a solid start in pursuit of the target and the visitors go the lunch on 47-0."
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Latest PostSeamers help Middlesex beat Sussex
Middlesex 234 & 331, Sussex 300 & 245
James Harris and Toby Roland-Jones starred with the ball as Middlesex beat Sussex by 20 runs at Lord's.
Steve Magoffin (5-73) took the final two Middlesex wickets quickly in the morning as they were bowled out for 331 - setting a target of 266.
Harris (4-57) ripped through Sussex's top order before Chris Nash (66) and Ben Brown took them to 163-5.
But once Roland-Jones (3-78) removed Nash, the visitors fell to 245 all out with Brown last man to go for 68.
O'Brien sets up rare Leics victory
Derbyshire 345 & 241, Leicestershire 314 & 273-7
A fine half-century from Niall O'Brien helped Leicestershire to a three-wicket win over Derbyshire at Grace Road.
Resuming on 56-4 chasing a target of 273, O'Brien and Aadil Ali extended their fifth-wicket stand to 138 before O'Brien was lbw to Mark Footitt for 87.
Ali (42) shared a fifty partnership with Andrea Agathangelou but both fell quickly to leave the hosts 238-7.
However, Ben Raine's 31 not out off 37 balls saw the Foxes to 273-7 and their second Division Two win of the season.
Rain delay at tense Lord's
Middlesex 234 & 331, Sussex 300 & 142-5
BBC London 94.9's Kevin Hand at Lord's:
"An early tea is being taken at Lord's after a sharp shower brought the players off with Sussex 142-5 having been set 266 to win.
"Chris Nash is leading the way with an unbeaten fifty after James Harris picked up three wickets to slow a rapid start to the chase.
"No further interruptions are expected and a result looks certain either way so Middlesex will hope for quick wickets on a pitch offering assistance to check the visitors' progress."
Notts wrap up comfortable win at Worcs
Worcestershire 269 & 292, Notts 330 & 234-5
Nottinghamshire have knocked off the 75 runs they needed to beat Worcestershire by five wickets at New Road.
After rain delayed the start until 12:15 BST, James Taylor and Riki Wessels added 31 runs in the morning to take Notts to 188-3 at lunch.
Saeed Ajmal removed Taylor for 66 and dismissed Wessels in his next over for 88 to leave the visitors 200-5.
But Samit Patel and Chris Read settled any nerves as they took Nottinghamshire to 234-5 and victory.
Hampshire claim second win of 2015
Hampshire 285 & 283-3 (dec), Warwickshire 125 & 227
Hampshire's survival fight was given a boost as they sealed a 216-run win over second-placed Warwickshire, whose own title ambitions took a setback.
The Bears resumed on 161-6 at the Ageas Bowl - still 283 runs off their target of 444 - and lost Rikki Clarke (55) to Jackson Bird's fourth ball of the day.
Fidel Edwards (4-55) took two more wickets to end with match figures of 9-87 as the visitors were out for 227.
Lunch: Notts close in on victory at New Road
Worcestershire 269 & 292, Notts 330 & 188-3
Only 45 minutes of play were possible in the morning session because of rain, but there was still time for Nottinghamshire to move within 44 runs of victory against Worcestershire.
Riki Wessels is unbeaten on 85 and James Taylor is 63 not out.
The pair have shared a fourth-wicket stand of 151 and look set to take Notts to their fourth Championship win of the summer.
Lunch: Second Foxes win on the cards
Derbyshire 345 & 241, Leicestershire 142-4
Niall O'Brien and Aadil Ali have put on 92 for the fifth wicket to keep Leicestershire's hopes of a second victory of the summer alive against Derbyshire.
The Foxes are 142-4 at lunch, needing 130 more runs for victory.
Lunch: Middlesex & Sussex both press for win
Middlesex 234 & 331, Sussex 300 & 68-3
BBC London 94.9's Kevin Hand at Lord's:
"Sussex have reached lunch on the final day at Lord's on 68-3 having been set a target of 266 to win.
"Dawid Malan was not out on 120 as Middlesex were bowled out for 331."
Lunch: Surrey set 313 to win by Essex
Essex 369 & 289-9 (dec), Surrey 346 & 47-0
BBC London 94.9's Mark Church at Colchester:
"All bubbling up nicely at Colchester. Essex declared after an hour's play after Gareth Batty's five wickets leaving a victory target of 313 for Surrey.
"Rory Burns and Zafar Ansari made a solid start in pursuit of the target and the visitors go the lunch on 47-0."
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Middlesex v Sussex - day four - BBC London 94.9
Essex v Surrey - day four - BBC Essex