Nelson had already been set to miss his first game since entering the NFL as the No. 6 pick in the 2018 draft when he was ruled out against the Miami Dolphins on Friday. He had started 51 games, plus three playoff contests, prior to this week.
He suffered the ankle injury in the first half of the Colts' Week 3 loss at the Tennessee Titans.
Losing Nelson, an All-Pro in each of his first three seasons, is a significant blow to an already struggling offensive line for the Colts, who have given up eight sacks and 31 quarterback hits through the first three weeks of the season.
Nelson's 75.5% run-block rate is first among NFL guards since entering the league, according to ESPN Stats & Information. His 95% pass block win rate is third among guards in that same span.
Chris Reed is expected to start at left guard for the Colts against the Dolphins.
"An elite leader, not just an elite player," coach Frank Reich said about Nelson. "We'll pick up the energy."
The Colts, who are trying to avoid their first 0-4 start since 2011, previously ruled out starting right tackle Braden Smith (foot/thumb), pass-rusher Kwity Paye (hamstring), cornerback Rock Ya-Sin (ankle) and safety Khari Willis (ankle/groin).
Information from ESPN's Mike Wells was used in this report.