Johnson made his playoff debut against the Cincinnati Bengals on January 7, 2012. In the game, Johnson had five receptions for 90 yards, including a 40-yard touchdown catch. The Texans won 31–10 and advanced to the divisional round where they fell to the Baltimore Ravens 20–13. Johnson caught eight passes for 111 yards in the losing effort. He was ranked 15th by his fellow players on the NFL Top 100 Players of 2012.
On October 14, 2012, Johnson became the first Texan in franchise history to reach the 10,000 receiving yards milestone during a Sunday Night Football loss to the Green Bay Packers in 2012.
On November 18, 2012, Johnson had the best game of his career in a Week 11 victory over the Jacksonville Jaguars. He had 14 receptions for 273 yards in that game, including the 48-yard game-winning touchdown in overtime. His receiving total was ninth-most in a game in NFL history and was the most for any receiver since Terrell Owens had 283 yards for the San Francisco 49ers in 2000. On November 22, Johnson had nine receptions for 188 yards in a Week 12 victory, again in overtime, over the Detroit Lions on Thanksgiving Thursday, crossing the 1,000 yards receiving mark for the sixth time in his career. Johnson set the NFL record for the highest receiving total in back-to-back games with 461 yards, beating the previous record of 450 yards set by Chad Johnson. Due to Johnson's efforts, he was named the AFC Offensive Player of the Month.
On December 4, 2012, Johnson made headlines around the world when it was shared that he spent over $19,000 for kids aged 8–16 in Child Protective Services to have a shopping spree at Toys R' Us. Johnson's own foundation, the Andre Johnson Charitable Foundation, funded the spree. The shopping spree is an event that Johnson partakes in yearly; however, due to a photo of him holding up lengthy receipts, this was the first year the shopping spree generated worldwide attention. After the spree, Johnson also joined the Houston Police Department's Blue Santa program to surprise 800 students at Houston's Bastian Elementary School with Christmas presents.