We aimed to examine the association between macronutrient and fatty acid intake and metabolic syndrome (MetS) and its components in South African male mini-bus taxi drivers. One hundred and eighty-five (n = 185) male taxi drivers, aged 20 years and older, who operate in the Cape Town metropole, South Africa, were included. The International Diabetes Federation (IDF) algorithm was used to define MetS. The association between macronutrient and fatty acid intake (assessed using 24 h recall) and MetS were analyzed using multivariable nutrient density substitution models. Overall, protein consumption significantly increased the likelihood of high blood pressure (HBP) and significantly lowered the likelihood of having low levels of high-density lipoprotein cholesterol (HDL-C). In an isoenergetic state, the intake of protein instead of carbohydrates (CHOs) and total fat, reduced the likelihood of elevated triglycerides by 6.7% and 6.6%, respectively. The intake of CHOs instead of protein and total fat, reduced the likelihood of HBP by 2.2% and 2.8%, respectively. In the same isoenergetic state, the intake of saturated fatty acids (SFAs) instead of mono-unsaturated fatty acids (MUFAs) increased the likelihood of HBP by 9.8%, whereas the intake of polyunsaturated fatty acids (PUFAs) instead of SFAs decreased the likelihood of HBP by 9.4%. The current study showed that when total food energy intake is kept constant, a diet that is high in protein, CHOs and PUFAs reduces triglycerides and BP, whereas the intake of total fat and SFAs had the opposite effect. It should, however, be noted that these outcomes were produced using mathematical models, as such we recommend further prospective studies in real life that will reveal the actual associations between the consumption of macronutrients and fatty acids and MetS and its components.