Higher alcohols like 1-butanol are considered important biofuels with superior properties compared to the more readily available bio-ethanol. An attractive route to prepare 1-butanol from ethanol is the Guerbet reaction. We here report the use of hydrotalcite-derived mono- (Cu-PMO or Ni-PMO) and bi-metallic (CuNi-PMO) porous metal oxide catalysts for the Guerbet coupling of ethanol to 1-butanol in a continuous flow reactor (320 °C, 0.1 MPa, LHSV = 15 mL g−1 h−1) at extended times on stream (~160 h). Two distinct regimes with different product distributions were observed for the Cu-PMO and CuNi-PMO catalyst with time on stream. At the start of the run, the initial conversion of ethanol dropped from about 85% to less than 20% after 60 h and acetaldehyde was the main product (regime 1). At prolonged times on stream (60–160 h), fairly constant low conversions of ethanol (14%) were observed and 1-butanol was the main product (regime 2). Performance of the monometallic Cu-PMO catalyst in terms of 1-butanol yield and stability was lower compared to the bi-metallic CuNi-PMO. Detailed catalyst characterization studies (XRD, H2-TPR, sorption of acrylic acid, TGA, TEM, HAADF-STEM, and EDS mapping) on both fresh and spent CuNi-PMO taken at various times on stream was performed to determine the changes in catalyst morphology and composition during a run, and particularly to obtain information on changes in catalyst structure operating in regime 1 or 2. The change in chemoselectivity is in line with an increase in basicity of the catalyst at extended runtimes.