On Thursday left back Sattar Zare was carried from the training field after twisting a knee while midfielder Ferydoon Zandi is still recovering from a fever.
"I'm scared it's not so good for both players and I'm not so sure they will be passed to play," said coach Branko Ivankovic.
With dynamic front-runner Ali Karimi and playmaker Mehdi Mahdavikia both returning from ankle and back trouble respectively, a double withdrawal raises doubts over Iran's ability to compete with the Group D seeds.
Iran are desperate for points against Mexico before facing group favourites Portugal and then Angola as they bid to reach the second-round knock-out stage for the first time in three attempts.
Sattar's injury came after Mexico's first-choice goalkeeper Oswaldo Sanchez flew home following his father's sudden death.
"It's a 1-1 draw now," quipped Ivankovic.