Steven Fletcher, who is more used to the role of lone striker, was partnered by Danny Graham for the first time as the former Swansea forward made his first start for the Black Cats.
Both came close to finding the back of the net - Fletcher hit the crossbar and Graham was inches away from turning in an effort from close range - but it fell to midfielder Stephane Sessegnon to score Sunderland's only goal in the 2-1 defeat at The Hawthorns.
However, despite his new attacking line failing to score, O'Neill believes they will soon click and become a strong partnership.
"It'll take a bit of time," O'Neill told the Sunderland Echo. "This was the first time that the two have played together competitively and I think they'll improve as time goes on and they get a proper understanding.
"All season long we have had Steven Fletcher playing as a centre-forward, but, in his time at Wolves, he played as many times off a centre-forward as he did as a centre-forward.
"And while he was enjoying it against Albion, he probably needed a bit of help closer to him during the game.
"I think they will do well, but Danny Graham is still working on getting his match sharpness. Because he hasn't played a lot this season compared to last, he feels he needs a game or two to get fully match fit.
"And that's fine - he worked hard for the side and he didn't have a great deal of luck - but he'll do fine for us."