This study analyzes 50 annual climate change indices related to temperature and precipitation in the Valley of Mexico basin for the period 1951–2010. First, a quality and homogenization analysis of 90 weather stations (categorized as urban, suburban, and rural) in the basin was performed using the Climatol algorithm. The non-parametric Mann–Kendall test and the Sen’s slope method were applied to determine the existence of a trend and to estimate the magnitude of the change in extreme climate indices, respectively. To eliminate the serial correlation problem, the lag-1 method and the Patakamuri tests were used. Statistically significant positive trends were found for SU, TMm, TNm, TNn, TX90p, and WSDI, as well as negative ones for FD, TX10p, TN10p, CSDI, and HDDheat18. The results seem to support an influence of anthropogenic global warming on the study region, rather than local effects of urbanization. However, it is likely that some significant differences in the urban change rate of some indices could be due to local effects, such as the difference in land cover that occurs between urban and rural stations. Not enough statistically significant results were found for the climate change indices related to precipitation in most of the stations. Compared to other studies in the Mexico City area, the main contribution of this study is the analysis of 50 climate indices in a 60-year period working with a quality-controlled and homogenized database.