Growth in pork production during the last decade in South Africa has escalated the risk of zoonotic pathogen emergence. This cross-sectional study was conducted to evaluate evidence for cross-species transmission of influenza A virus between pigs and swine workers. Between February and October 2018, samples from swine workers and pigs were collected from three farms in KwaZulu-Natal Province, South Africa. Workers nasal washes and serum samples, and swine oral secretion samples (rope sampling method) were studied for evidence of swine influenza A virus infection using molecular and serological methods. Among 84 human nasal washes and 51 swine oral secretion specimens, 44 (52.4%) and 6 (11.8%) had molecular evidence of influenza A virus. Microneutralization assays with workers´ enrollment sera against swine H1N1 and H3N2 viruses revealed a high prevalence of elevated antibodies. Multivariate risk factor analysis showed that male workers from the age-group quartile 23 to 32 years, who self-reported a recent history of exposure to someone with influenza disease and seldom use of personal protective equipment were at highest risk of molecular detection of influenza A virus. These pilot study data suggest that influenza A viruses are likely highly prevalent on South African swine farms. South Africa would benefit from periodic surveillance for novel influenza viruses, as well as education and seasonal influenza vaccine programs for swine workers.