Climate change extremes are now a contemporary issue. The Intergovernmental Panel on Climate Change acknowledges that evidence on trends in public health threats, including infectious diseases resulting from climate change, exists. The groups most affected by climate change are those with less ability to adapt to changes, and thus causing concern for their health. There are also several studies in Sub-Saharan Africa that are aimed at understanding the morbidity and mortality of diarrhea, pneumonia and malaria. Nevertheless, literature on the understanding of the relationship between climate change and the occurrence of diarrhea, pneumonia and malaria are limited. This study therefore sought to bridge this gap by exploring the relationship between climate change and the occurrence of infectious diseases (i.e., diarrhea, pneumonia and malaria) in Tanga, Tanzania. The study adopted a longitudinal study design using the Health Management Information System (HMIS) data in Tanga and Handeni districts, Tanzania, for the period between January 2016 and December 2018. While, the monthly climate change data (i.e., precipitation, humidity and temperature) for the same period were retrieved from the Tanzania Meteorological Authority (TMA). The data were analyzed using Multilevel Mixed-Effects Negative Binomial Regression (MMENBR) to assess the association between climate change indicators and the infectious diseases as well regional differences (i.e., Tanga and Handeni districts) using STATA version 13. The analysis showed a significant relationship between climate change and the occurrence of infectious diseases. There were mean differences in the climate indicators and in the occurrence of infectious diseases between Tanga and Handeni districts among all the age groups except for the newborns (i.e., < 1 month) in different years. The trend differences, between the two district, in the occurrence of infectious diseases and climate indicators were also statistically significant. There was an association between precipitation and an increased rate of diarrhea without dehydration (Adjusted incidence rate ratio, IRR = 1.01; 95% Confidence interval, CI: 1.00 – 1.01; p ≤ 0.10) and diarrhea with dehydration (Adjusted IRR = 1.01; 95% CI: 1.01 – 1.02; p ≤ 0.01), and a reduced rate of malarial infections (Adjusted IRR = 0.99; 95% CI: 0.99 – 0.99; p ≤ 0.001). The relationship between humidity levels and the occurrence of diarrhea without dehydration (Adjusted IRR = 0.98; 95% CI: 0.97 – 0.99; p ≤ 0.05), severe diarrhea (Adjusted IRR = 1.03; 95% CI: 1.01 – 1.06; p ≤ 0.05), non-severe pneumonia (Adjusted IRR = 1.01; 95% CI: 1.01 – 1.02; p ≤ 0.05) and severe pneumonia (Adjusted IRR = 1.02; 95% CI: 1.01 – 1.03; p ≤ 0.05) were statistically significant. On the other hand, an increase in the maximum temperature was associate with an increased incidence of diarrhea with severe dehydration (Adjusted IRR = 1.13; 95% CI: 1.01 – 1.27; p ≤ 0.05) and malaria as diagnosed using blood smear technique (Adjusted IRR = 1.18; 95% CI: 1.03 – 1.35; p ≤ 0.05). Furthermore, the minimum temperature was associated with increased rates of malaria as diagnosed using rapid diagnostic test (Adjusted IRR = 1.23; 95% CI: 1.09 – 1.39; p ≤ 0.001). The rates of malaria were in the opposing directions when using blood smear and rapid diagnostic test for the different temperature indicators (i.e., maximum and minimum temperature). In conclusion, there was an association between climate change and the rates of infectious diseases in Tanga and Handeni districts, Tanzania. The results of this study have critical policy implications for health intervention programs and resource allocation during the different seasons. The health facilities should be well equipped while at the same time health professionals should be prepared to handle the major infectious diseases in the different seasons of the year.