Excessive use of agro-chemicals (such as mineral fertilizers) poses potential risks to soil quality. Application of organic amendments and reduction of inorganic fertilizer are economically feasible and environmentally sound approaches to develop sustainable agriculture. This study investigated and evaluated the effects of mineral fertilizer reduction and partial substitution of organic amendment on soil fertility and heavy metal content in a 10-season continually planted vegetable field during 2009–2012. The experiment included four treatments: 100% chemical fertilizer (CF100), 80% chemical fertilizer (CF80), 60% chemical fertilizer and 20% organic fertilizer (CF60+OM20), and 40% chemical fertilizer and 40% organic fertilizer (CF40+OM40). Soil nutrients, enzyme activity and heavy metal content were determined. The results showed that single chemical fertilizer reduction (CF80) had no significant effect on soil organic matter content, soil catalase activity and soil heavy metal content, but slightly reduced soil available N, P, K, and soil urease activity, and significantly reduced soil acid phosphatase activity. Compared with CF100, 40 or 60% reduction of chemical fertilizer supplemented with organic fertilizer (CF60+OM20, CF40+OM40) significantly increased soil organic matter, soil catalase activity and urease activity especially in last several seasons, but reduced soil available P, K, and soil acid phosphatase activity. In addition, continuous application of organic fertilizer resulted in higher accumulation of Zn, Cd, and Cr in soil in the late stage of experiment, which may induce adverse effects on soil health and food safety.