Mackail-Smith suffered an Achilles injury against Bristol City on Tuesday night and will undergo surgery early next week.
Manager Gus Poyet had already lost fellow forward Will Hoskins to a knee injury and is now preparing to dip into the loan market for attacking reinforcements.
"We have two weeks of the loan window left and we cannot afford to finish the season with just two strikers," he said.
"We are still there or thereabouts and there are options, but it's complicated.
"We have lost Macca so we'll see first if we can get that 'in-behind' option, which is needed. If not, then the player might depend on the way that we are playing or the teams we're playing against.
"Every player we are looking at is different and in a different situation. Some are not playing because others are playing better, some because they are coming back from injury and some because they are too expensive.
"None are the same and we cannot just get anyone, so we'll keep working."