Nayak decided to take on full-time anti-superstition activism in 2004 when he heard that a girl had been sacrificed in Gulbarga in Karnataka. He was an assistant professor of biochemistry when he took voluntary retirement on 25 November 2006, after working there for 28 years.
Before the general election in 2009, Nayak laid an open challenge to any soothsayer to answer 25 questions correctly about the forthcoming elections. The prize was set at  (about ). About 450 responses were mailed to him, but none were found to be correct. The Federation of Indian Rationalist Associations has been conducting such challenges since 1991. During May 2013 Karnataka state assembly election, disappointed at the challenge being one-sided, Nayak had decided against the idea of challenging astrologers this time. But when a Bengaluru-based astrologer Shankar Hegde made claims to predict the election results accurately, he received the challenge. Nayak offered to hand over a cheque of Rs.10 lakh (after deducting taxes as applicable under income Tax Act), if 19 out of the 20 results were proven right. However, later on astrologer Hegde did not turn up.
Through the organisation named Aid Without Religion which was registered in July 2011, he has been helping people and institutions where there are no religious rituals, superstitious practices, unscientific systems of medicine and such supernatural beliefs. The registration was done at Rahu Kalam, a time of the day which is the most inauspicious – so it was a double rather a triple whammy, a Saturday, new moon day that too in the month of Ati which is considered to be the most unlucky time and at Rahu Kalam!
He has been featured on National Geographics television show Is it real?'. He has also appeared on the Discovery Channel. He has been a regular columnist at the newspaper Mangalore Today since its inception. He also serves on the editorial board of the Folks Magazine.
He has admitted to have been attacked for his activism a few times. He also has stated that his scooter's brake wires were once found severed, after an astrologer predicted his death or injury. He was a close associate to Gauri Lankesh, M. M. Kalburgi, and Narendra Dabholkar; all three like-minded and were assassinated in a more-or-less similar fashion.
He was also involved in fighting against Midbrain activation, an alleged modern technique that enables students to see objects despite being blindfolded.
In March 2017, there was an attempt on Narendra Nayaks life. During the early morning hours, while on his way to the Mangala swimming pool in his car, he was approached by two unidentified men in a bike wearing helmets and hinted that his tyres were punctured. An unfazed Nayak suspected foul play and with a great presence of mind drove all the way to a nearby gas station and saw that everything was in order. He immediately filed a Police Complain. Nayak suspected that this attempt on his life could possibly be the repercussions to his fight for the justice of the slain RTI activist Vinayak Baliga, who was murdered exactly a year previous to this episode. Nayaks personal gunman was on holidays. Nayak continues to have personal gunman handed over by Mangalore Police till date. 
Narendra presented at the first Global Congress on Scientific Thinking and Action which was held on March 17–20, 2021. During Session III on Alternative Medicine, he talked about the wide use of alternative medicines in India, including homeopathy, and said that various alternative treatments are often claimed to be Indian in origin. In addition, he states that the relatively low death rate from COVID in India has been falsely attributed to the use of homeopathic medicines as preventative. When asked what should be done about the use of alternative medicines in India, he said, flatly, “They should be banned.”