Resource-deprived coastal peri-urban settlements in Southern Ghana are characterized by indiscriminate solid waste disposal and open defecation practices. Persons engaged in waste handling in such communities perform their activities with little or no personal protective equipment. They are thus confronted with the risk of faecal pollution of the hands and other bodily parts. A mixed method approach was used to investigate 280 waste handlers performing different activities to estimate recent faecal pollution of their hands and to observe the utilization of personal protective equipment and sanitation/hygiene facilities during work. The log concentration of E. coli on hands of waste handlers after work (8.60 ± 4.20 CFU/hand, mean ± standard deviation) was significantly higher compared with the E. coli log concentration before work (2.95 ± 1.89 CFU/hand, mean ± standard deviation) (p<0.001). The odds of faecal pollution was significantly higher (aOR 4.2; 95% CI: 1.9–9.1) for workers aged 35 years and above compared with those less than 35 years; and for workers at public toilet facilities (aOR 3.0; 95% CI: 1.0–8.4) compared with those who worked for private waste handling companies. Female workers were, however, 60% less likely (aOR 0.4; 95% CI: 0.2–0.8) to experience faecal pollution of their hands compared with males. The workers had limited access to water and sanitation and hygiene facilities, and about one-fifth (n = 59; 21.1%) did not use personal protective equipment during work. Waste handlers should be provided and instructed in proper use of personal protective equipment, have access to sanitation facilities and adopt improved hygiene behaviour to avoid the risk of faecal pollution and associated disease risk.