Barcelona confirmed on Thursday that Pique sprained a ligament in his right ankle in the match against City and will be out for three weeks, while Alba has a left hamstring problem and will be sidelined for two weeks - meaning both will miss the trip to the Etihad Stadium.
"It's always worrying when you lose players through injury," Luis Enrique said.
There are three games remaining in the group stages and Barcelona, who have a perfect record and are five points clear at the top of Group C, will seal their place in the next round if they beat City on Nov. 1.
"I'm certain we will find it difficult in Manchester," added the coach.
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Despite Barcelona's injury woes, the real battle in Group C is for second place. Pep Guardiola's City is second with four points and Borussia Monchengladbach have three following their 2-0 win at bottom-placed Celtic, who have one point.
For Luis Enrique, the most encouraging aspect of Barca's performance was seeing Lionel Messi complete a hat-trick in his first start following a three-week break with a groin injury.
"It doesn't matter if he is coming off an injury, he is the interpretation of total football," Luis Enrique said.
The five-times world player of the year scored a hat-trick for the second time in the Champions League this season and the seventh time in the competition.
Messi, who had come on as a substitute and scored one goal in Barca's 4-0 win over Deportivo La Coruna at the weekend, wrote on his Facebook account: "What a great way to return to UEFA Champions League action with an important win, a big effort from the whole team and our fans."
Barca are fourth in La Liga and play away to Valencia on Saturday.
(Reporting by Adriana Garcia, editing by Pritha Sarkar)
