COVID-19 has become a threat to the existence of man as no method of effective treatment has been found. Although the WHO has given guidelines that include physical distancing to prevent the spread of COVID-19, it is not feasible in practice with commercial motorcycle operation, which is a major source of income and means of transportation in Nigeria. We examined the COVID-19 knowledge, awareness, and preventive practices among commercial motorcycle operators (CMOs) and the potentials for community transmission of SARS-CoV-2 in the South-South region of Nigeria. Data used was collected from a cross-sectional survey of 777 CMOs operating in the South-South region of Nigeria. The instrument captured information on their biodata, knowledge, awareness, and preventive practices of COVID-19. The data obtained were subjected to both descriptive and inferential analyses using SAS JMP Statistical Discovery™ software version 14.3 (SAS Institute, Cary, North Carolina, USA). The majority of the CMOs were of age category 26–35 years (36.4%), married (82.1%), under a monogamous union (83.8%), had 3–4 children (43.4%) and resided in rural areas (60.8%). The mean years of experience of the CMOs was 4.9 ± 2.45 years with most depending on daily income of N1,000–2,000 (87.6%). All the CMOs were aware of the existence of COVID-19, but 93.3% of them did not believe it existed in their state. Only 37.8% of them put on facemasks while on duty, although they were aware that they could be infected or infect others in the community. Prevention practices among CMOs were significantly predicted by age category, type of family, number of dependents, and place of residence. We conclude that CMOs have high potentials for transmission of SARS-CoV-2 in the communities because the business does not permit physical distancing. It is recommended that guidelines requiring mandatory screening of operators and riders be implemented.