A previous study conducted in Yaoundé, Cameroon, showed a significant increase in ciprofloxacin-resistant Neisseria gonorrhoeae. Still, ciprofloxacin is the recommended first-line medication for gonorrhoea in Cameroon. We aimed to provide further evidence of increasing resistance of N. gonorrhoeae to ciprofloxacin. We conducted a retrospective study (2012–2018) and retrieved coded patient and specimen real-world data from the Centre Pasteur du Cameroun’s laboratory information system and laboratory worksheets. We included disc diffusion method results for tetracycline, azithromycin, and spectinomycin, and minimal inhibitory concentrations obtained by E-test for ciprofloxacin, ceftriaxone, and benzylpenicillin. A total of 449 N. gonorrhoeae were isolated; a higher proportion of them presented resistance to ciprofloxacin (64.4%), benzylpenicillin (80.1%), and tetracycline (58.4%). The resistance to ciprofloxacin increased significantly (p < 0.0001) from 15.0% in 2012 to 79.5% in 2018. Since 2016 a significant decrease (p = 0.002) in resistance to benzylpenicillin occurred and the resistance to tetracycline remained stable. The level of resistance to ceftriaxone (1.8%), azithromycin (2.1%), and spectinomycin (2.0%) was low. Our study confirms that ciprofloxacin is not recommended as a first-line treatment for gonorrhoea. It also illustrates the urgent need to establish a robust and sustainable gonococcal antimicrobial surveillance programme to guide national treatment guidelines in order to control gonorrhoea in Cameroon.