We present results from a comprehensive analysis of mid-infrared imaging of Neptune’s atmosphere. Using all currently available ground-based images, we show how Neptune’s mid-infrared emission has changed over the past decades in images sensitive to stratospheric ethane, methane, and temperatures. Neptune’s stratospheric thermal emission appears to vary significantly on sub-seasonal timescales of years or less with significant latitudinal asymmetry not predicted by seasonal radiative and photochemical models. In particular, Neptune’s stratospheric temperatures have declined globally since 2003, although northern and southern latitudes varied separately. In just the past few years, Neptune’s south polar region has dramatically brightened while the remainder of the stratosphere has grown colder. These collective observations provide the strongest evidence to date that processes produce significant variability in Neptune’s stratosphere on sub-seasonal timescales.