A popular approach in the investigation of the short-term behavior of a non-stationary time series is to assume that the time series decomposes additively into a long-term trend and short-term fluctuations. A first step towards investigating the short-term behavior requires estimation of the trend, typically via smoothing in the time domain. We propose a method for time-domain smoothing, called complexity-regularized regression (CRR). This method extends recent work, which infers a regression function that makes residuals from a model “look random”. Our approach operationalizes non-randomness in the residuals by applying ideas from computational mechanics, in particular the statistical complexity of the residual process. The method is compared to generalized cross-validation (GCV), a standard approach for inferring regression functions, and shown to outperform GCV when the error terms are serially correlated. Regression under serially-correlated residuals has applications to time series analysis, where the residuals may represent short timescale activity. We apply CRR to a time series drawn from the Dow Jones Industrial Average and examine how both the long-term and short-term behavior of the market have changed over time.