Pharmacies are the frontline of the pandemic and critical to maintaining public health. The emergence of COVID-19 brought unprecedented challenges and changes to all nations of the world. In the light of this, this study assessed the challenges of pharmaceutical practices in Nigeria during COVID-19. A descriptive cross-sectional survey design was adopted, and the data were collected from 1,200 respondents through the interview schedule and structured questionnaire using a systematic random sampling technique. A total of 1,118 copies of the questionnaire were retrieved, coded, and analysed using descriptive and inferential statistics aided by the SPSS software version 23. The study discovered different factors that influenced the effective practice of pharmacists during the COVID-19 pandemic. The findings of this study revealed that the majority, 591(52.9%) of the pharmacists, encountered difficulties on the road with security personnel while on essential duty and also found it ‘somewhat difficult to work during the pandemic. The results of Factor Analysis grouped the major challenges into material and financial constraints. The results showed two orthogonal factors pharmaceutical practices, which were derived with the total explanation of 65.35% of the variance. Only variables with constraints loadings of 0.70 and above were used in naming the constraints. The material constraint has the greatest impact on effective practices of pharmacists to provide treatment for illnesses during COVID-19 with a 44.16% contribution. There is a need for government and institution supports for better and effective pharmaceutical practices before, during, and after any sort of pandemic, especially in drugs supplies and financial assistance. Keywords: Assessment, Challenges, COVID-19 Pandemic, Pharmaceutical Practices, Nigeria.