The Spanish, European and world champions completely dominated their La Liga rivals, victory made all the sweeter when talisman Messi came off the bench to add two goals to first-half strikes from the former Arsenal captain.
Barca had said Messi would miss the game with flu but the Argentine World Player of the Year was able to replace Pedro for the final half-hour against an outclassed Osasuna.
Fabregas, who was at Barca's youth school with Messi before moving to London, put the home side ahead in the 13th minute.
"I didn't vomit and there was no fever, I just had a stomach ache, nothing more," Messi said in a television interview.
"That's why I couldn't take part in this morning's training but later on I recovered enough to be able to play."
Barring upsets in next week's second legs, Barca face a quarter-final clash with bitter rivals Real Madrid, who beat them 1-0 in last year's final.
Jose Mourinho's side came back from two goals down to win their last 16 first leg against Malaga 3-2 on Tuesday.
Real Sociedad, King's Cup winners in 1987, took the upper hand against Real Mallorca when they beat the 2003 champions 2-0 at their Anoeta stadium in San Sebastian earlier on Wednesday.
There were surprise results in Tuesday's other three games.
Valencia host 2010 winners Sevilla and Espanyol play at second-division Cordoba in Thursday's remaining two first legs.
