Purpose The purpose of this paper is to examine the effects of protean career orientation (PCO) and psychological capital (PsyCap) on well-being among knowledge workers. Design/methodology/approach The author adopted a two-wave cross-lagged design. In total, 518 knowledge workers at three enterprises in China were sampled to complete the Direnzo et al.'s (2015) Protean Career Orientation Questionnaire, Luthans et al.'s (2007) Psychological Capacity Questionnaire, and Ryff and Keyes' (1995) Psychological Well-Being Scale. The main statistical methods involved descriptive statistics, structural equation modeling, and bootstrapping analysis. Findings The findings of the study were as follows: PCO positively predicted PsyCap among knowledge workers; both PCO and PsyCap positively contributed to knowledge workers' well-being; and knowledge workers' PsyCap partially mediated the relationship between their PCO and well-being. Originality/value Rare empirical studies were conducted on the relationship between PCO and psychological well-being. The previous findings are inconsistent on whether PCO is an antecedent of PsyCap, or PsyCap is an antecedent of PCO. The author conducted a cross-lagged survey to examine the above relationships; to certain extent, the present study addresses the research gap and contributes to the burgeoning literature.