The hosts deservedly hit the front at a bristling El Sadar thanks to Unai Garcia's header, but Isco finished with aplomb in the 33rd minute.
Sergio Ramos' knack for vital goals came up trumps for Zinedine Zidane once more before the interval, and Madrid now lead Barcelona by six points at the summit.
Substitutes Lucas Vazquez and Luka Jovic made sure of that state of affairs before Quique Setien takes Barca to face his old employers Real Betis in the day's late kick-off.
Right-back Nacho Vidal fizzed a 20-yard shot narrowly wide inside the first minute to serve notice of Osasuna's intentions before Jose Arnaiz and Ruben Garcia raided down the right-hand side of Madrid's defence to go close.
It meant the 14th-minute opener was on the cards when it arrived – Unai Garcia stooping to head home Ruben Garcia's corner.
Madrid's most immediate route back into the match appeared to be Osasuna keeper Sergio Herrera, who twice darted from his goal and was indebted to last-ditch clearances from shots by Karim Benzema and Dani Carvajal.
Herrera was more conventionally placed but had no chance when Isco dispatched a looping ball on the volley after Gareth Bale's attempt was blocked.
Casemiro atoned for his poor marking on Osasuna's goal by heading Luka Modric's corner back across goal for Ramos to make it 2-1.
Unai Garcia got in the way of Benzema's goalbound 49th-minute effort from a Modric cutback, and Osasuna kept scrapping away – Casemiro turning Ruben Garcia's shot behind after Nacho Vidal ransacked Isco.
The playmaker was certainly more at home in the opposition half and a sharp low stop from Herrera kept out an Isco snapshot before Vazquez replaced Bale.
The Spain winger benefitted from Benzema's unselfish 84th-minute pass, while Modric and Federico Valverde combined for Jovic to rifle in his second LaLiga goal – and first since October – in stoppage time.
Inigo Perez rattling Thibaut Courtois crossbar showed Osasuna's spirit remained intact until the last.
What does it mean? Pressure on Barca
Madrid might not have been at their best here, but it does not matter. Barcelona's uncertain start to life under Setien will now continue with them eyeing a mounting deficit when they kick-off at Estadio Benito Villamarin. Anything more than three points for the Blaugrana and this weekend will come to appear pivotal in the title battle.
Ramos proves the master of irritation once more
He is certainly not to everyone's taste, but if you're a fan, this was time to enjoy some pure, unadulterated, hook-it-to-my-veins Sergio Ramos. Madrid were lucky to be level when Ramos decided to begin a prolonged argument with any Osasuna player willing to listen.
The trap of distraction was set for the corner to come and the unmarked skipper proceeded to mock his opponents by sucking his thumb and blowing kisses in celebration. In a title race that could be scrapped for until the last, Madrid have the ideal man leading the charge.
Lack of sharpness does Bale no favours
Claiming an assist for Isco's equaliser would be ambitious, but Bale needs all he can get at Madrid right now. Granted only a 10th LaLiga start this term, the Wales star volleyed into the side-netting and headed over from Carvajal deliveries before half-time. They were, at best, half-chances but Bale's dwindling standing with Zidane means he now needs something special every time an opportunity comes his way.
Madrid host Celta Vigo in seven days' time, when Osasuna travel to Athletic Bilbao.