But all it takes is one signature win to swiftly turn around a player's fortunes.
It was another snag in the return for world number 13 Djokovic, who admitted he lacked composure while playing in just his second event of 2018 and first since having surgery.
After losing to Hyeon Chung in the fourth round of the Australian Open, Djokovic took some time to get himself healthy. He suffered his first opening-round loss in the California desert since his debut in 2006. Mayer was supposed to play Kei Nishikori in his second-round match, but the former US Open finalist withdrew from the tournament due to illness.
"I just completely lost rhythm, everything", said Djokovic. I'm just so used to the courts here.
It appears as if Novak Djokovic faces a long and hard road back to his glory days on the tennis tour. He denied a set point while serving down 2-5 in the opener and immediately broke the former World No. 1 in the next game, firing a backhand victor down the line and a forehand pass off a poor smash.
"I like both but I think Nadal is more like my gamestyle", Thiem told ESPN. Keeping it simple and maintaing a consistent plan of attack, Daniel worked Djokovic from corner to corner.
Holder Roger Federer avoided the same fate as Djokovic, though the Swiss top seed was pushed by left-handed Argentine Federico Delbonis in a match that was completed on Sunday after being halted by rain at 2-2 in the second set the previous day.
The world No.1 - who has a ideal 13-0 record this year - is the defending champion and is bidding for a sixth Indian Wells title.
South African seventh seed Kevin Anderson also prevailed in his second round match, 7-5 6-4 over Russian Evgeny Donskoy.
The 30-year-old crashed out of the first ATP World Tour Masters 1000 of the calendar year following his defeat at the hands of Taro Daniel.
Speaking after his upset win, Daniel said the Djokovic he bounded out of the tournament was not the one the tennis world is used to admiring. He has since reached the quarter-finals at the Citi Open in Washington and hoisted the trophy on home soil at the Pune Challenger in November.
The Indian Bhambri will meet 18th-seeded Sam Querrey in the third round after the big-serving American accounted for Germany's Mischa Zverev 6-4 7-5. The two instead played Sunday afternoon and Stephens looked very sharp in dispatching Azarenka 6-1, 7-5.