Abstract Background The frequency and mechanisms of persistent health complaints attributed to tick bites or tick-borne diseases are unknown. We evaluate such complaints in Norwegian cases and controls. Methods People older than 18 years with persistent health complaints of six months or more attributed to tick bites or tick-borne diseases (cases) were recruited into a nationwide cross-sectional study between October 2016 and January 2021. Demographic data, tick bites, antibiotic use, and tick-borne pathogen serology were recorded. We evaluated somatic symptoms (PHQ-15), fatigue (Fatigue Severity Scale), mental and physical health (RAND-36), affective symptoms (HAD Scale) and modern health worries (MHW Scale) as outcome measures. Serological tests included IgG antibodies against B. burgdorferi (Bb) and other tick-borne pathogens. The control population (n = 2803) was recruited from a tick-endemic region in Søgne, southern Norway. Differences between cases and controls were evaluated. Results A total of 500 responses were collected through general practitioners (n = 14), by invitation (n = 94), and by Short Message Service (SMS) (n = 392). The estimate of prevalence is based on 392 of 270.000 included by SMS (0.15%). The SMS cohort reported better physical health than those recruited by invitation. Cases had significantly more somatic and affective symptoms, fatigue, comorbidities, and reduced quality of life related to health than controls. The differences in fatigue and physical health between cases and controls were not related to previous tick exposures. Bb IgG and other antibodies against tick-borne pathogens were more prevalent in cases than controls. In multivariable analyses, cases that were never treated did not exhibit higher somatic symptom scores compared to those treated multiple times. Seropositive Bb cases had worse mental health (p < 0.001) and more depressive symptoms (p = 0.017) than seronegative cases. Conclusions The crude prevalence of persistent health complaints in Norway attributed to tick bites or tick-borne diseases is 0.15%. The cases reported significantly poorer physical health, including increased fatigue, when compared to the controls. These relationships were not affected by tick exposures. However, poorer mental health in cases may be associated with Bb seropositivity, especially for the ones with comorbidities. In conclusion, no clear associations were found between tick bites, tick-borne diseases and persistent health complaints.