Purpose Neck pain is common among office workers and leads to work productivity loss. This study aimed to investigate the effect of a multi-component intervention on neck pain-related work productivity loss among Swiss office workers. Methods Office workers, aged 18–65 years, and without serious neck-related health problems were recruited from two organisations for our stepped-wedge cluster randomized controlled trial. The 12-week multi-component intervention included neck exercises, health-promotion information, and workplace ergonomics. The primary outcome of neck pain-related work productivity loss was measured using the Work Productivity and Activity Impairment Questionnaire and expressed as percentages of working time. In addition, we reported the weekly monetary value of neck pain-related work productivity loss. Data was analysed on an intention-to-treat basis using a generalized linear mixed-effects model. Results Data from 120 participants were analysed with 517 observations. At baseline, the mean age was 43.7 years (SD 9.8 years), 71.7% of participants were female (N = 86), about 80% (N = 95) reported mild to moderate neck pain, and neck pain-related work productivity loss was 12% of working time (absenteeism: 1.2%, presenteeism: 10.8%). We found an effect of our multi-component intervention on neck pain-related work productivity loss, with a marginal predicted mean reduction of 2.8 percentage points (b = −0.27; 95% CI: −0.54 to −0.001, p = 0.049). Weekly saved costs were Swiss Francs 27.40 per participant. Conclusions: Our study provides evidence for the effectiveness of a multi-component intervention to reduce neck pain-related work productivity loss with implications for employers, employees, and policy makers.Trial Registration ClinicalTrials.gov, NCT04169646. Registered 15 November 2019—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646.