Weather and air quality conditions have been anecdotally reported to be related to symptom fluctuations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but this has never been empirically investigated. This exploratory study aims to examine the effects of weather and air quality on daily fluctuations of chronic pain and fatigue in women with ME/CFS. In an intensive longitudinal design, 58 participants with ME/CFS provided daily pain and fatigue ratings for an average of 61 days. Daily weather and air quality data were obtained from the National Oceanic and Atmospheric Administration and the US Environmental Protection Agency for the Birmingham, AL area. Linear mixed models revealed a significant relationship between days with more severe pain and worse Air Quality Indices (AQI, p < 0.001), lower wind speeds (p = 0.009), greater particulate matter (p = 0.037), and lower carbon monoxide (p = 0.004), sulfur dioxide (p = 0.003), and ozone levels (p = 0.015). Greater fatigue was associated with more particulates (p = 0.023) and lower barometric pressure (p = 0.048). These results suggest that air quality and weather can have small effects on ME/CFS symptom severity.