Although an independent role for several important lifestyle factors in the aetiology of metabolic syndrome (MetS) has been established, less is known about their combined effects. We aimed to investigate the association of the combined role of recognised lifestyle factors, expressed as a healthy lifestyle score (HLS), and the risk of MetS in Tehranian adults. A total of 3480 participants without MetS were recruited from among participants of the Tehran Lipid and Glucose Study (2009-2011) and followed a mean of 6 years. Dietary data were collected using a validated food frequency questionnaire at baseline. We determined HLS in three ways among the participants based on four factors including, no current smoking, no obesity, vigorous physical activity and a healthy dietary pattern (assessed by either the alternate healthy eating index-2010 [AHEI-2010], the modified French Programme National Nutrition Santé-Guideline Score [mPNNS-GS] or the healthy diet pattern score [HDP]). All three indices consisted of the four factors including smoking (yes/no), physical activity (active/inactive), obesity (yes/no) and diet quality. Mean ± SD age of participants (43.5% men) was 38.7 ± 13.0 years. During the study follow-up, 558 (16.0%) new cases of MetS were identified. In the age- and sex-adjusted model, there was a negative relationship between the higher score of HLS-AHEI-2010 (OR = 0.42; 95% CI: 0.29-0.60), HLS-mPNNS-GS (OR = 0.45; 95% CI: 0.33-0.62) and HLS-HDP (OR = 0.70; 95% CI: 0.52-0.93) with the risk of MetS (p for trend <0.05). In the multivariable model, after adjustment for confounding variables, the risk of MetS decreased across tertiles of HLS-AHEI-2010 (OR = 0.48; 95% CI: 0.33-0.70, p for trend <0.001), HLS-mPNNS-GS (OR = 0.50; 95% CI: 0.36-0.69, p for trend <0.001) and HLS-HDP (OR = 0.67; 95% CI: 0.49-0.90, p for trend: 0.008). The findings of the current study highlight that greater adherence to modifiable healthy lifestyle factors scores is associated with a decreased risk of MetS.